Neurology Reviews

I was (probably) the bane of my elementary school nurse.

I hated PE (I know, who didn’t?). But I also had childhood asthma. So it was an easy out to go to the school nurse, Mrs. Reed, because I was having an asthma attack, or at least claiming to have one.

She’d put me in a chair to “keep an eye” on me, occasionally have me take the prescription drug my pediatrician had ordered (Marax – anyone else remember that?), and knew to send me back to class about 5 minutes before PE was over.

Maybe Mrs. Reed liked me. Maybe it was just the path of least resistance to let me dodge PE. Maybe she’d hated PE, too, and was sympathetic. Who knows?

So twice a week through years of elementary school she and I went through the same routine of my showing up in her office. No matter how busy she was, she always told me to take a seat and do a therapeutic application of her stethoscope. She often told others who noticed my frequent visits that I was “a sickly child” even though I knew she saw through me and said it with a sense of sarcasm and humor.

Of course, life goes on, and one day 20 years ago Mrs. Reed showed up on my hospital census as a new consult after she’d had a minor stroke.

She remembered me very well. Her first comment, said with the same tone I recalled, was that she was amazed I’d lived to adulthood after having been such “a sickly child.” We both laughed.

Now, in her late 80s, she still comes to see me for this and that. Sometimes we reminisce about the intertwined journey our lives have taken us on. Sometimes she asks if I’ve been to PE recently.

Like any patient, she occasionally shows up on the wrong day, or at the wrong time. I always do my best to see her, though.

After all, I owe her big time for letting me dodge PE.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I was (probably) the bane of my elementary school nurse.

I hated PE (I know, who didn’t?). But I also had childhood asthma. So it was an easy out to go to the school nurse, Mrs. Reed, because I was having an asthma attack, or at least claiming to have one.

She’d put me in a chair to “keep an eye” on me, occasionally have me take the prescription drug my pediatrician had ordered (Marax – anyone else remember that?), and knew to send me back to class about 5 minutes before PE was over.

Maybe Mrs. Reed liked me. Maybe it was just the path of least resistance to let me dodge PE. Maybe she’d hated PE, too, and was sympathetic. Who knows?

So twice a week through years of elementary school she and I went through the same routine of my showing up in her office. No matter how busy she was, she always told me to take a seat and do a therapeutic application of her stethoscope. She often told others who noticed my frequent visits that I was “a sickly child” even though I knew she saw through me and said it with a sense of sarcasm and humor.

Of course, life goes on, and one day 20 years ago Mrs. Reed showed up on my hospital census as a new consult after she’d had a minor stroke.

She remembered me very well. Her first comment, said with the same tone I recalled, was that she was amazed I’d lived to adulthood after having been such “a sickly child.” We both laughed.

Now, in her late 80s, she still comes to see me for this and that. Sometimes we reminisce about the intertwined journey our lives have taken us on. Sometimes she asks if I’ve been to PE recently.

Like any patient, she occasionally shows up on the wrong day, or at the wrong time. I always do my best to see her, though.

After all, I owe her big time for letting me dodge PE.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I was (probably) the bane of my elementary school nurse.

I hated PE (I know, who didn’t?). But I also had childhood asthma. So it was an easy out to go to the school nurse, Mrs. Reed, because I was having an asthma attack, or at least claiming to have one.

She’d put me in a chair to “keep an eye” on me, occasionally have me take the prescription drug my pediatrician had ordered (Marax – anyone else remember that?), and knew to send me back to class about 5 minutes before PE was over.

Maybe Mrs. Reed liked me. Maybe it was just the path of least resistance to let me dodge PE. Maybe she’d hated PE, too, and was sympathetic. Who knows?

So twice a week through years of elementary school she and I went through the same routine of my showing up in her office. No matter how busy she was, she always told me to take a seat and do a therapeutic application of her stethoscope. She often told others who noticed my frequent visits that I was “a sickly child” even though I knew she saw through me and said it with a sense of sarcasm and humor.

Of course, life goes on, and one day 20 years ago Mrs. Reed showed up on my hospital census as a new consult after she’d had a minor stroke.

She remembered me very well. Her first comment, said with the same tone I recalled, was that she was amazed I’d lived to adulthood after having been such “a sickly child.” We both laughed.

Now, in her late 80s, she still comes to see me for this and that. Sometimes we reminisce about the intertwined journey our lives have taken us on. Sometimes she asks if I’ve been to PE recently.

Like any patient, she occasionally shows up on the wrong day, or at the wrong time. I always do my best to see her, though.

After all, I owe her big time for letting me dodge PE.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

It’s Oscars weekend, so for the second annual Meddy Awards – a very self-congratulatory and very tongue-in-cheek version of the Oscars – we celebrate outstanding medical performances and events in motion pictures throughout history. Without further ado (or comedy skits or musical numbers or extended tributes or commercials), the Meddys go to ...

Best depiction of emergency medicine’s rollercoaster

M*A*S*H (1970)

The original film, not the TV show, jumps from Frank Burns being hauled away in a straitjacket to a soldier’s spurting neck wound. Hawkeye Pierce calmly steps in and we see the entire sequence of him applying pressure, then stepping back to gown-and-glove (“it’s going to spurt a bit”), then jumping back in with arterial sutures, quipping, “Baby, we’re gonna see some stitchin’ like you never saw before.” After that, cocktail hour. Yes, medicine in Hollywood can be overdramatized and even inaccurate, but Robert Altman’s take on the novel by former U.S. Army surgeon Richard Hooker still stands tall for just how crazy emergency medicine can be.

Best ‘is there a doctor in the house?’ moment

Field of Dreams (1989)

When Ray Kinsella’s daughter gets knocked off the back of the bleachers, everything stops. No one knows what to do … except Doc “Moonlight” Graham, who gives up his life’s (and afterlife’s) dream to step off the field and save the girl from choking to death. Burt Lancaster, in his final movie role, embodies everything people wish a doctor to be: Calm, kind, and able to offer a quick, effective solution to a crisis. “Hey rookie! You were good.” Yes, he sure was.

Most unethical doctor

Elvis (2022)

No doctor wants to be remembered as the guy who killed Elvis. But that legacy clings to Dr. George Nichopoulos, Elvis’s personal physician in the 1970s. In Elvis, Dr. Nichopoulos, played by Tony Nixon, hovers in the background, enabling the King’s worsening addictions. Taking late-night calls for narcotics and injecting the unconscious star with stimulants, “unethical” is an understatement for the fictional “Dr. Nick.” The real Dr. Nichopoulos was acquitted of wrongdoing in Elvis’ death, although there is little doubt that the thousands of medication doses he prescribed played a role. When his license was finally revoked for overprescribing in the 1990s, the obliging doc reportedly claimed, “I cared too much.”

Best self-use of a defibrillator

Casino Royale (2006)

We expect backlash in the post-award press conference since James Bond technically only attempted to self-defibrillate in the passenger seat of his car. He never attached the device to the leads. Vesper Lynd had to pick up his slack and save the day. Also, supporters of fellow self-defibrillating nominee Jason Statham in Crank will no doubt raise a stink on Twitter. But we stand by our choice because it was such an, ahem, heart-stopper of a scene.

Best worst patient lying about an injury

Tár (2022)

Love it or hate it, few recent movies have been as polarizing as Tár. Cate Blanchett’s portrayal of a musical genius might be toweringly brilliant or outrageously offensive (or both) depending on whom you ask. But clearly the character has a loose relationship with facts. More than a few doctors might have raised an eyebrow had Lydia Tár appeared with injuries to her face, claiming to have been attacked in a mugging. In reality, Lydia tripped and fell while pursuing an attractive young cellist into a hazardous basement. Did she lie to protect her image, preserve her marriage, or – like many patients – avoid a lecture on unhealthy behavior? We pick D, all of the above.

Best therapy for a speech disorder

The King’s Speech (2010)

Public speaking might cause anxiety for many of us, but how about doing it in front of a global radio audience while wrestling with a speech disorder? Based on a true story, The King’s Speech revealed that terrifying experience for England’s King George VI. Enter Lionel Logue, played by Geoffrey Rush. Irreverent, unconventional, and untrained, the Australian pioneer in speech and language therapy uses a range of strategies – some of which are still used today – to help the royal find his voice. But when singing, shouting swear words, and provoking rage don’t do the trick, Mr. Logue turns to psychotherapy to unearth the childhood traumas at the root of the king’s disability. Experience, as Mr. Logue tells his patient, matters just as much as “letters after your name.”

A version of this article first appeared on Medscape.com.

It’s Oscars weekend, so for the second annual Meddy Awards – a very self-congratulatory and very tongue-in-cheek version of the Oscars – we celebrate outstanding medical performances and events in motion pictures throughout history. Without further ado (or comedy skits or musical numbers or extended tributes or commercials), the Meddys go to ...

Best depiction of emergency medicine’s rollercoaster

M*A*S*H (1970)

The original film, not the TV show, jumps from Frank Burns being hauled away in a straitjacket to a soldier’s spurting neck wound. Hawkeye Pierce calmly steps in and we see the entire sequence of him applying pressure, then stepping back to gown-and-glove (“it’s going to spurt a bit”), then jumping back in with arterial sutures, quipping, “Baby, we’re gonna see some stitchin’ like you never saw before.” After that, cocktail hour. Yes, medicine in Hollywood can be overdramatized and even inaccurate, but Robert Altman’s take on the novel by former U.S. Army surgeon Richard Hooker still stands tall for just how crazy emergency medicine can be.

Best ‘is there a doctor in the house?’ moment

Field of Dreams (1989)

When Ray Kinsella’s daughter gets knocked off the back of the bleachers, everything stops. No one knows what to do … except Doc “Moonlight” Graham, who gives up his life’s (and afterlife’s) dream to step off the field and save the girl from choking to death. Burt Lancaster, in his final movie role, embodies everything people wish a doctor to be: Calm, kind, and able to offer a quick, effective solution to a crisis. “Hey rookie! You were good.” Yes, he sure was.

Most unethical doctor

Elvis (2022)

No doctor wants to be remembered as the guy who killed Elvis. But that legacy clings to Dr. George Nichopoulos, Elvis’s personal physician in the 1970s. In Elvis, Dr. Nichopoulos, played by Tony Nixon, hovers in the background, enabling the King’s worsening addictions. Taking late-night calls for narcotics and injecting the unconscious star with stimulants, “unethical” is an understatement for the fictional “Dr. Nick.” The real Dr. Nichopoulos was acquitted of wrongdoing in Elvis’ death, although there is little doubt that the thousands of medication doses he prescribed played a role. When his license was finally revoked for overprescribing in the 1990s, the obliging doc reportedly claimed, “I cared too much.”

Best self-use of a defibrillator

Casino Royale (2006)

We expect backlash in the post-award press conference since James Bond technically only attempted to self-defibrillate in the passenger seat of his car. He never attached the device to the leads. Vesper Lynd had to pick up his slack and save the day. Also, supporters of fellow self-defibrillating nominee Jason Statham in Crank will no doubt raise a stink on Twitter. But we stand by our choice because it was such an, ahem, heart-stopper of a scene.

Best worst patient lying about an injury

Tár (2022)

Love it or hate it, few recent movies have been as polarizing as Tár. Cate Blanchett’s portrayal of a musical genius might be toweringly brilliant or outrageously offensive (or both) depending on whom you ask. But clearly the character has a loose relationship with facts. More than a few doctors might have raised an eyebrow had Lydia Tár appeared with injuries to her face, claiming to have been attacked in a mugging. In reality, Lydia tripped and fell while pursuing an attractive young cellist into a hazardous basement. Did she lie to protect her image, preserve her marriage, or – like many patients – avoid a lecture on unhealthy behavior? We pick D, all of the above.

Best therapy for a speech disorder

The King’s Speech (2010)

Public speaking might cause anxiety for many of us, but how about doing it in front of a global radio audience while wrestling with a speech disorder? Based on a true story, The King’s Speech revealed that terrifying experience for England’s King George VI. Enter Lionel Logue, played by Geoffrey Rush. Irreverent, unconventional, and untrained, the Australian pioneer in speech and language therapy uses a range of strategies – some of which are still used today – to help the royal find his voice. But when singing, shouting swear words, and provoking rage don’t do the trick, Mr. Logue turns to psychotherapy to unearth the childhood traumas at the root of the king’s disability. Experience, as Mr. Logue tells his patient, matters just as much as “letters after your name.”

A version of this article first appeared on Medscape.com.

It’s Oscars weekend, so for the second annual Meddy Awards – a very self-congratulatory and very tongue-in-cheek version of the Oscars – we celebrate outstanding medical performances and events in motion pictures throughout history. Without further ado (or comedy skits or musical numbers or extended tributes or commercials), the Meddys go to ...

Best depiction of emergency medicine’s rollercoaster

M*A*S*H (1970)

The original film, not the TV show, jumps from Frank Burns being hauled away in a straitjacket to a soldier’s spurting neck wound. Hawkeye Pierce calmly steps in and we see the entire sequence of him applying pressure, then stepping back to gown-and-glove (“it’s going to spurt a bit”), then jumping back in with arterial sutures, quipping, “Baby, we’re gonna see some stitchin’ like you never saw before.” After that, cocktail hour. Yes, medicine in Hollywood can be overdramatized and even inaccurate, but Robert Altman’s take on the novel by former U.S. Army surgeon Richard Hooker still stands tall for just how crazy emergency medicine can be.

Best ‘is there a doctor in the house?’ moment

Field of Dreams (1989)

When Ray Kinsella’s daughter gets knocked off the back of the bleachers, everything stops. No one knows what to do … except Doc “Moonlight” Graham, who gives up his life’s (and afterlife’s) dream to step off the field and save the girl from choking to death. Burt Lancaster, in his final movie role, embodies everything people wish a doctor to be: Calm, kind, and able to offer a quick, effective solution to a crisis. “Hey rookie! You were good.” Yes, he sure was.

Most unethical doctor

Elvis (2022)

No doctor wants to be remembered as the guy who killed Elvis. But that legacy clings to Dr. George Nichopoulos, Elvis’s personal physician in the 1970s. In Elvis, Dr. Nichopoulos, played by Tony Nixon, hovers in the background, enabling the King’s worsening addictions. Taking late-night calls for narcotics and injecting the unconscious star with stimulants, “unethical” is an understatement for the fictional “Dr. Nick.” The real Dr. Nichopoulos was acquitted of wrongdoing in Elvis’ death, although there is little doubt that the thousands of medication doses he prescribed played a role. When his license was finally revoked for overprescribing in the 1990s, the obliging doc reportedly claimed, “I cared too much.”

Best self-use of a defibrillator

Casino Royale (2006)

We expect backlash in the post-award press conference since James Bond technically only attempted to self-defibrillate in the passenger seat of his car. He never attached the device to the leads. Vesper Lynd had to pick up his slack and save the day. Also, supporters of fellow self-defibrillating nominee Jason Statham in Crank will no doubt raise a stink on Twitter. But we stand by our choice because it was such an, ahem, heart-stopper of a scene.

Best worst patient lying about an injury

Tár (2022)

Love it or hate it, few recent movies have been as polarizing as Tár. Cate Blanchett’s portrayal of a musical genius might be toweringly brilliant or outrageously offensive (or both) depending on whom you ask. But clearly the character has a loose relationship with facts. More than a few doctors might have raised an eyebrow had Lydia Tár appeared with injuries to her face, claiming to have been attacked in a mugging. In reality, Lydia tripped and fell while pursuing an attractive young cellist into a hazardous basement. Did she lie to protect her image, preserve her marriage, or – like many patients – avoid a lecture on unhealthy behavior? We pick D, all of the above.

Best therapy for a speech disorder

The King’s Speech (2010)

Public speaking might cause anxiety for many of us, but how about doing it in front of a global radio audience while wrestling with a speech disorder? Based on a true story, The King’s Speech revealed that terrifying experience for England’s King George VI. Enter Lionel Logue, played by Geoffrey Rush. Irreverent, unconventional, and untrained, the Australian pioneer in speech and language therapy uses a range of strategies – some of which are still used today – to help the royal find his voice. But when singing, shouting swear words, and provoking rage don’t do the trick, Mr. Logue turns to psychotherapy to unearth the childhood traumas at the root of the king’s disability. Experience, as Mr. Logue tells his patient, matters just as much as “letters after your name.”

A version of this article first appeared on Medscape.com.

NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.

The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
 

Missed primary endpoint blamed on low events

The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.

India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.

“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.

In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).

In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
 

Enoxaparin and apixaban are studied

In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).

The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.

The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).

Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).

The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
 

Bleeding rates did not differ between arms

Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.

Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.

Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.

“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.

COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.

“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”

Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.

NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.

The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
 

Missed primary endpoint blamed on low events

The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.

India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.

“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.

In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).

In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
 

Enoxaparin and apixaban are studied

In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).

The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.

The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).

Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).

The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
 

Bleeding rates did not differ between arms

Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.

Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.

Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.

“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.

COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.

“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”

Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.

NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.

The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
 

Missed primary endpoint blamed on low events

The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.

India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.

“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.

In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).

In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
 

Enoxaparin and apixaban are studied

In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).

The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.

The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).

Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).

The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
 

Bleeding rates did not differ between arms

Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.

Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.

Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.

“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.

COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.

“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”

Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.

This discussion was recorded on Feb. 21, 2023. This transcript has been edited for clarity.

Robert D. Glatter, MD: Welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Joining me today is Gilberto Salazar, MD, an emergency physician at UT Southwestern Medical Center in Dallas, to discuss a new virtual reality tool to help health care providers deescalate workplace violence. Welcome, Dr. Salazar. It’s a pleasure to have you join us today.

Gilberto A. Salazar, MD: The pleasure is all mine, Dr. Glatter. Thank you so much for having me.

Dr. Glatter: This is such an important topic, as you can imagine. Workplace violence is affecting so many providers in hospital emergency departments but also throughout other parts of the hospital.

First, can you describe how the virtual reality (VR) program was designed that you developed and what type of situations it simulates?

Dr. Salazar: We worked in conjunction with the University of Texas at Dallas. They help people like me, subject matter experts in health care, to bring ideas to reality. I worked very closely with a group of engineers from their department in designing a module specifically designed to tackle, as you mentioned, one of our biggest threats in workplace violence.

We decided to bring in a series of competencies and proficiencies that we wanted to bring into the virtual reality space. In leveraging the technology and the expertise from UT Dallas, we were able to make that happen.

Dr. Glatter: I think it’s important to understand, in terms of virtual reality, what type of environment the program creates. Can you describe what a provider who puts the goggles on is experiencing? Do they feel anything? Is there technology that enables this?

Dr. Salazar: Yes, absolutely. We were able to bring to reality a series of scenarios very common from what you and I see in the emergency department on a daily basis. We wanted to immerse a learner into that specific environment. We didn’t feel that a module or something on a computer or a slide set could really bring the reality of what it’s like to interact with a patient who may be escalating or may be aggressive.

UT Dallas

UT Southwestern Medical Center

We were able to create our own algorithm, but it’s not brand new. We’re just borrowing what we think is the best to create something that the majority of health care personnel are going to be able to relate to and be able to really be proficient at.

This includes things like active listening, bargaining, how to respond, where to put yourself in a situation, and the best possible situation to respond to a scenario, how to prevent things – how to get out of a chokehold, for example. We’re borrowing from several different disciplines and creating something that can be very concise and organized.

Dr. Glatter: Does this program that you’ve developed allow the provider to get feedback in the sense that when they’re in such a danger, their life could be at risk? For example, if they don’t remove themselves in a certain amount of time, this could be lethal.

Dr. Salazar: Yes, 100%. Probably the one thing that differentiates our project from any others is the ability to customize the experience so that a learner who is doing the things that we ask them to do in terms of safety and response is able to get out of a situation successfully within the environment. If they don’t, they get some kind of feedback.

Not to spoil the surprise here, but we’re going to be doing things like looking at decibel meters to see what the volume in the room is doing and how you’re managing the volume and the stimulation within the room. If you are able to maintain the decibel readings at a specific level, you’re going to succeed through the module. If you don’t, we keep the patient escalation going.

Dr. Glatter: There is a debrief built into this type of approach where, in other words, learning points are emphasized – where you could have done better and such.

Dr. Salazar: Yes, absolutely. We are going to be able to get individualized data for each learner so that we can tailor the debrief to their own performance and be able to give them actionable items to work on. It’s a debrief that’s productive and individualized, and folks can walk away with something useful in the end.

Dr. Glatter: Are the data shared or confidential at present?

Dr. Salazar: At this very moment, the data are confidential. We are going to look at how to best use this. We’re hoping to eventually write this up and see how this information can be best used to train personnel.

Eventually, we may see that some of the advice that we’re giving is very common to most folks. Others may require some individualized type of feedback. That said, it remains to be seen, but right now, it’s confidential.

Dr. Glatter: Is this currently being implemented as part of your curriculum for emergency medicine residents?

Dr. Salazar: We’re going to study it first. We’re very excited to include our emergency medicine residents as one of our cohorts that’s going to be undergoing the module, and we’re going to be studying other forms of workplace violence mitigation strategies. We’re really excited about the possibility of this eventually becoming the standard of education for not only our emergency medicine residents, but also health care personnel all over the world.

Dr. Glatter: I’m glad you mentioned that, because obviously nurses, clerks in the department, and anyone who’s working in the department, for that matter, and who interfaces with patients really should undergo such training.

Dr. Salazar: Absolutely. The folks at intake, at check-in, and at kiosks. Do they go through a separate area for screening? You’re absolutely right. There are many folks who interface with patients and all of us are potential victims of workplace violence. We want to give our health care family the best opportunity to succeed in these situations.

Dr. Glatter:: Absolutely. Even EMS providers, being on the front lines and encountering patients in such situations, would benefit, in my opinion.

Dr. Salazar: Yes, absolutely. Behavioral health emergencies and organically induced altered mental status results in injury, both physical and mental, to EMS professionals as well, and there’s good evidence of that. I’ll be very glad to see this type of education make it out to our initial and continuing education efforts for EMS as well.

Dr. Glatter: I want to thank you. This has been very helpful. It’s such an important task that you’ve started to explore, and I look forward to follow-up on this. Again, thank you for your time.

Dr. Salazar: It was my pleasure. Thank you so much for having me.
 

Dr. Glatter is an attending physician at Lenox Hill Hospital in New York City and assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, N.Y. He is an editorial adviser and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes. Dr. Salazar is a board-certified emergency physician and associate professor at UT Southwestern Medicine Center in Dallas. He is involved with the UTSW Emergency Medicine Education Program and serves as the medical director to teach both initial and continuing the emergency medicine education for emergency medical technicians and paramedics, which trains most of the Dallas Fire Rescue personnel and the vast majority for EMS providers in the Dallas County. In addition, he serves as an associate chief of service at Parkland’s emergency department, and liaison to surgical services. A version of this article originally appeared on Medscape.com.

This discussion was recorded on Feb. 21, 2023. This transcript has been edited for clarity.

Robert D. Glatter, MD: Welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Joining me today is Gilberto Salazar, MD, an emergency physician at UT Southwestern Medical Center in Dallas, to discuss a new virtual reality tool to help health care providers deescalate workplace violence. Welcome, Dr. Salazar. It’s a pleasure to have you join us today.

Gilberto A. Salazar, MD: The pleasure is all mine, Dr. Glatter. Thank you so much for having me.

Dr. Glatter: This is such an important topic, as you can imagine. Workplace violence is affecting so many providers in hospital emergency departments but also throughout other parts of the hospital.

First, can you describe how the virtual reality (VR) program was designed that you developed and what type of situations it simulates?

Dr. Salazar: We worked in conjunction with the University of Texas at Dallas. They help people like me, subject matter experts in health care, to bring ideas to reality. I worked very closely with a group of engineers from their department in designing a module specifically designed to tackle, as you mentioned, one of our biggest threats in workplace violence.

We decided to bring in a series of competencies and proficiencies that we wanted to bring into the virtual reality space. In leveraging the technology and the expertise from UT Dallas, we were able to make that happen.

Dr. Glatter: I think it’s important to understand, in terms of virtual reality, what type of environment the program creates. Can you describe what a provider who puts the goggles on is experiencing? Do they feel anything? Is there technology that enables this?

Dr. Salazar: Yes, absolutely. We were able to bring to reality a series of scenarios very common from what you and I see in the emergency department on a daily basis. We wanted to immerse a learner into that specific environment. We didn’t feel that a module or something on a computer or a slide set could really bring the reality of what it’s like to interact with a patient who may be escalating or may be aggressive.

UT Dallas

UT Southwestern Medical Center

We were able to create our own algorithm, but it’s not brand new. We’re just borrowing what we think is the best to create something that the majority of health care personnel are going to be able to relate to and be able to really be proficient at.

This includes things like active listening, bargaining, how to respond, where to put yourself in a situation, and the best possible situation to respond to a scenario, how to prevent things – how to get out of a chokehold, for example. We’re borrowing from several different disciplines and creating something that can be very concise and organized.

Dr. Glatter: Does this program that you’ve developed allow the provider to get feedback in the sense that when they’re in such a danger, their life could be at risk? For example, if they don’t remove themselves in a certain amount of time, this could be lethal.

Dr. Salazar: Yes, 100%. Probably the one thing that differentiates our project from any others is the ability to customize the experience so that a learner who is doing the things that we ask them to do in terms of safety and response is able to get out of a situation successfully within the environment. If they don’t, they get some kind of feedback.

Not to spoil the surprise here, but we’re going to be doing things like looking at decibel meters to see what the volume in the room is doing and how you’re managing the volume and the stimulation within the room. If you are able to maintain the decibel readings at a specific level, you’re going to succeed through the module. If you don’t, we keep the patient escalation going.

Dr. Glatter: There is a debrief built into this type of approach where, in other words, learning points are emphasized – where you could have done better and such.

Dr. Salazar: Yes, absolutely. We are going to be able to get individualized data for each learner so that we can tailor the debrief to their own performance and be able to give them actionable items to work on. It’s a debrief that’s productive and individualized, and folks can walk away with something useful in the end.

Dr. Glatter: Are the data shared or confidential at present?

Dr. Salazar: At this very moment, the data are confidential. We are going to look at how to best use this. We’re hoping to eventually write this up and see how this information can be best used to train personnel.

Eventually, we may see that some of the advice that we’re giving is very common to most folks. Others may require some individualized type of feedback. That said, it remains to be seen, but right now, it’s confidential.

Dr. Glatter: Is this currently being implemented as part of your curriculum for emergency medicine residents?

Dr. Salazar: We’re going to study it first. We’re very excited to include our emergency medicine residents as one of our cohorts that’s going to be undergoing the module, and we’re going to be studying other forms of workplace violence mitigation strategies. We’re really excited about the possibility of this eventually becoming the standard of education for not only our emergency medicine residents, but also health care personnel all over the world.

Dr. Glatter: I’m glad you mentioned that, because obviously nurses, clerks in the department, and anyone who’s working in the department, for that matter, and who interfaces with patients really should undergo such training.

Dr. Salazar: Absolutely. The folks at intake, at check-in, and at kiosks. Do they go through a separate area for screening? You’re absolutely right. There are many folks who interface with patients and all of us are potential victims of workplace violence. We want to give our health care family the best opportunity to succeed in these situations.

Dr. Glatter:: Absolutely. Even EMS providers, being on the front lines and encountering patients in such situations, would benefit, in my opinion.

Dr. Salazar: Yes, absolutely. Behavioral health emergencies and organically induced altered mental status results in injury, both physical and mental, to EMS professionals as well, and there’s good evidence of that. I’ll be very glad to see this type of education make it out to our initial and continuing education efforts for EMS as well.

Dr. Glatter: I want to thank you. This has been very helpful. It’s such an important task that you’ve started to explore, and I look forward to follow-up on this. Again, thank you for your time.

Dr. Salazar: It was my pleasure. Thank you so much for having me.
 

Dr. Glatter is an attending physician at Lenox Hill Hospital in New York City and assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, N.Y. He is an editorial adviser and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes. Dr. Salazar is a board-certified emergency physician and associate professor at UT Southwestern Medicine Center in Dallas. He is involved with the UTSW Emergency Medicine Education Program and serves as the medical director to teach both initial and continuing the emergency medicine education for emergency medical technicians and paramedics, which trains most of the Dallas Fire Rescue personnel and the vast majority for EMS providers in the Dallas County. In addition, he serves as an associate chief of service at Parkland’s emergency department, and liaison to surgical services. A version of this article originally appeared on Medscape.com.

This discussion was recorded on Feb. 21, 2023. This transcript has been edited for clarity.

Robert D. Glatter, MD: Welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Joining me today is Gilberto Salazar, MD, an emergency physician at UT Southwestern Medical Center in Dallas, to discuss a new virtual reality tool to help health care providers deescalate workplace violence. Welcome, Dr. Salazar. It’s a pleasure to have you join us today.

Gilberto A. Salazar, MD: The pleasure is all mine, Dr. Glatter. Thank you so much for having me.

Dr. Glatter: This is such an important topic, as you can imagine. Workplace violence is affecting so many providers in hospital emergency departments but also throughout other parts of the hospital.

First, can you describe how the virtual reality (VR) program was designed that you developed and what type of situations it simulates?

Dr. Salazar: We worked in conjunction with the University of Texas at Dallas. They help people like me, subject matter experts in health care, to bring ideas to reality. I worked very closely with a group of engineers from their department in designing a module specifically designed to tackle, as you mentioned, one of our biggest threats in workplace violence.

We decided to bring in a series of competencies and proficiencies that we wanted to bring into the virtual reality space. In leveraging the technology and the expertise from UT Dallas, we were able to make that happen.

Dr. Glatter: I think it’s important to understand, in terms of virtual reality, what type of environment the program creates. Can you describe what a provider who puts the goggles on is experiencing? Do they feel anything? Is there technology that enables this?

Dr. Salazar: Yes, absolutely. We were able to bring to reality a series of scenarios very common from what you and I see in the emergency department on a daily basis. We wanted to immerse a learner into that specific environment. We didn’t feel that a module or something on a computer or a slide set could really bring the reality of what it’s like to interact with a patient who may be escalating or may be aggressive.

UT Dallas

UT Southwestern Medical Center

We were able to create our own algorithm, but it’s not brand new. We’re just borrowing what we think is the best to create something that the majority of health care personnel are going to be able to relate to and be able to really be proficient at.

This includes things like active listening, bargaining, how to respond, where to put yourself in a situation, and the best possible situation to respond to a scenario, how to prevent things – how to get out of a chokehold, for example. We’re borrowing from several different disciplines and creating something that can be very concise and organized.

Dr. Glatter: Does this program that you’ve developed allow the provider to get feedback in the sense that when they’re in such a danger, their life could be at risk? For example, if they don’t remove themselves in a certain amount of time, this could be lethal.

Dr. Salazar: Yes, 100%. Probably the one thing that differentiates our project from any others is the ability to customize the experience so that a learner who is doing the things that we ask them to do in terms of safety and response is able to get out of a situation successfully within the environment. If they don’t, they get some kind of feedback.

Not to spoil the surprise here, but we’re going to be doing things like looking at decibel meters to see what the volume in the room is doing and how you’re managing the volume and the stimulation within the room. If you are able to maintain the decibel readings at a specific level, you’re going to succeed through the module. If you don’t, we keep the patient escalation going.

Dr. Glatter: There is a debrief built into this type of approach where, in other words, learning points are emphasized – where you could have done better and such.

Dr. Salazar: Yes, absolutely. We are going to be able to get individualized data for each learner so that we can tailor the debrief to their own performance and be able to give them actionable items to work on. It’s a debrief that’s productive and individualized, and folks can walk away with something useful in the end.

Dr. Glatter: Are the data shared or confidential at present?

Dr. Salazar: At this very moment, the data are confidential. We are going to look at how to best use this. We’re hoping to eventually write this up and see how this information can be best used to train personnel.

Eventually, we may see that some of the advice that we’re giving is very common to most folks. Others may require some individualized type of feedback. That said, it remains to be seen, but right now, it’s confidential.

Dr. Glatter: Is this currently being implemented as part of your curriculum for emergency medicine residents?

Dr. Salazar: We’re going to study it first. We’re very excited to include our emergency medicine residents as one of our cohorts that’s going to be undergoing the module, and we’re going to be studying other forms of workplace violence mitigation strategies. We’re really excited about the possibility of this eventually becoming the standard of education for not only our emergency medicine residents, but also health care personnel all over the world.

Dr. Glatter: I’m glad you mentioned that, because obviously nurses, clerks in the department, and anyone who’s working in the department, for that matter, and who interfaces with patients really should undergo such training.

Dr. Salazar: Absolutely. The folks at intake, at check-in, and at kiosks. Do they go through a separate area for screening? You’re absolutely right. There are many folks who interface with patients and all of us are potential victims of workplace violence. We want to give our health care family the best opportunity to succeed in these situations.

Dr. Glatter:: Absolutely. Even EMS providers, being on the front lines and encountering patients in such situations, would benefit, in my opinion.

Dr. Salazar: Yes, absolutely. Behavioral health emergencies and organically induced altered mental status results in injury, both physical and mental, to EMS professionals as well, and there’s good evidence of that. I’ll be very glad to see this type of education make it out to our initial and continuing education efforts for EMS as well.

Dr. Glatter: I want to thank you. This has been very helpful. It’s such an important task that you’ve started to explore, and I look forward to follow-up on this. Again, thank you for your time.

Dr. Salazar: It was my pleasure. Thank you so much for having me.
 

Dr. Glatter is an attending physician at Lenox Hill Hospital in New York City and assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, N.Y. He is an editorial adviser and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes. Dr. Salazar is a board-certified emergency physician and associate professor at UT Southwestern Medicine Center in Dallas. He is involved with the UTSW Emergency Medicine Education Program and serves as the medical director to teach both initial and continuing the emergency medicine education for emergency medical technicians and paramedics, which trains most of the Dallas Fire Rescue personnel and the vast majority for EMS providers in the Dallas County. In addition, he serves as an associate chief of service at Parkland’s emergency department, and liaison to surgical services. A version of this article originally appeared on Medscape.com.

NEW ORLEANS - The antipsychotic brexpiprazole effectively improves agitation associated with Alzheimer’s disease (AD) with favorable tolerability, results of a phase 3 study suggest.

“In this phase 3 trial of patients with agitation in Alzheimer’s dementia, treatment with brexpiprazole 2 or 3 mg/day resulted in statistically significantly greater improvements in agitation versus placebo on the primary and key secondary endpoints,” said study investigator George Grossberg, MD, professor and director of the division of geriatric psychiatry, department of psychiatry & behavioral neuroscience, Saint Louis University.

Dr. Grossberg presented the findings as part of the annual meeting of the American Association for Geriatric Psychiatry.

Agitation common, distressing

With two previous studies also showing efficacy of brexpiprazole in AD-related agitation, Dr. Grossberg speculated that brexpiprazole will become the first drug to be approved for agitation in AD.

Agitation is one of the most common AD symptoms and is arguably the most distressing for patients and caregivers alike, Dr. Grossberg noted.

The drug was approved by the Food and Drug Administration in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.

To investigate the drug at effective doses for AD-related agitation, the researchers conducted a phase 3 multicenter trial that included 345 patients with AD who met criteria for agitation and aggression.

Study participants had a mean Mini-Mental State Examination (MMSE) score between 5 and 22 at screening and baseline and a mean Cohen-Mansfield Agitation Inventory (CMAI) total score of about 79. A score above 45 is considered clinically significant agitation. Use of AD medications were permitted.

Patients had a mean age of 74 years and were randomly assigned in a 2:1 ratio to receive treatment with brexpiprazole 2 mg (n = 75) or 3 mg (n = 153) per day, or placebo (n = 117).

The study’s primary endpoint was improvement as assessed by the CMAI. Over 12 weeks, participants in the brexpiprazole group experienced greater improvement in agitation, with a mean change of –22.6 with brexpiprazole vs. –17.3 with placebo (P = .0026).

Brexpiprazole was also associated with significantly greater improvement in the secondary outcome of change from baseline to week 12 in agitation severity, as assessed using the Clinical Global Impression-Severity of Illness (CGI-S) score (mean change, –1.20 with brexpiprazole vs. –0.93 with placebo; P = .0078).

Specifically, treatment with the drug resulted in improvements in three key subscales of agitation, including aggressive behavior, such as physically striking out (P < .01 vs. placebo); physically nonaggressive; and verbally agitated, such as screaming or cursing (both P < .05).

Treatment-emergent adverse events (TEAEs) associated with brexpiprazole vs. placebo included somnolence (3.5% vs. 0.9%), nasopharyngitis (3.1% vs. 1.7%), dizziness (2.7% vs. 1.7%), diarrhea (2.2% vs. 0.9%), urinary tract infection (2.2% vs. 0.9%), and asthenia (2.2% vs. 0.0%).

“Aside from headache, no other TEAEs had an incidence of more than 5% in the brexpiprazole (2 or 3 mg) group, or in either dose group,” Dr. Grossberg said. “Cognition also remained stable,” he added.

Boxed warnings

Adverse events commonly associated with brexpiprazole include weight change, extrapyramidal events, falls, cardiovascular events, and sedation. In the study, all occurred at an incidence of less than 2% in both study groups, he noted.

Compared with the antipsychotic aripiprazole, brexpiprazole is associated with lower weight gain and akathisia, or motor restlessness.

One death occurred in the brexpiprazole 3 mg group in a patient who had heart failure, pneumonia, and cachexia. At autopsy, it was found the patient had cerebral and coronary atherosclerosis. The death was considered to be unrelated to brexpiprazole, said Dr. Grossberg.

This finding is notable because a caveat is that brexpiprazole, like aripiprazole and other typical and atypical antipsychotics, carries an FDA boxed warning related to an increased risk for death in older patients when used for dementia-related psychosis.

Noting that a black box warning about mortality risk is not a minor issue, Dr. Grossberg added that the risks are relatively low, whereas the risks associated with agitation in dementia can be high.

“If it’s an emergency situation, you have to treat the patient because otherwise they may harm someone else, or harm the staff, or harm their loved ones or themselves, and in those cases, we want to treat the patient first, get them under control, and then we worry about the black box,” he said.

In addition, “the No. 1 reason for getting kicked out of a nursing home is agitation or severe behaviors in the context of a dementia or a major neurocognitive disorder that the facility cannot control,” Dr. Grossberg added.

In such cases, patients may wind up in an emergency department and may not be welcome back at the nursing home.

“There’s always a risk/benefit ratio, and I have that discussion with patients and their families, but I can tell you that I’ve never had a family ask me not to use a medication because of the black box warning, because they see how miserable and how out of control their loved one is and they’re miserable because they see the suffering and will ask that we do anything that we can to get this behavior under control,” Dr. Grossberg said.

Caution still warranted

Commenting on the study, Rajesh R. Tampi, MD, professor and chairman of the department of psychiatry and the Bhatia Family Endowed Chair in Psychiatry at Creighton University, Omaha, Neb., underscored that, owing to the concerns behind the FDA warnings, “nonpharmacologic management is the cornerstone of treating agitation in Alzheimer’s dementia.”

He noted that the lack of an FDA-approved drug for agitation with AD is the result of “the overall benefits of any of the drug classes or drugs trialed to treat agitation in Alzheimer’s dementia vs. their adverse effect profile,” he said.

Therefore, he continued, “any medication or medication class should be used with caution among these individuals who often have polymorbidity.”

Dr. Tampi agreed that “the use of each drug for agitation in AD should be on a case-by-case basis with a clear and documented risk/benefit discussion with the patient and their families.”

“These medications should only be used for refractory symptoms or emergency situations where the agitation is not managed adequately with nonpharmacologic techniques and with a clear and documented risk/benefit discussion with patients and their families,” Dr. Tampi said. 

The study was supported by Otsuka Pharmaceutical Development & Commercialization and H. Lundbeck. Dr. Grossberg has received consulting fees from Acadia, Avanir, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda. Dr. Tampi had no disclosures to report.

A version of this article first appeared on Medscape.com.

This article was updated 3/14/23.

NEW ORLEANS - The antipsychotic brexpiprazole effectively improves agitation associated with Alzheimer’s disease (AD) with favorable tolerability, results of a phase 3 study suggest.

“In this phase 3 trial of patients with agitation in Alzheimer’s dementia, treatment with brexpiprazole 2 or 3 mg/day resulted in statistically significantly greater improvements in agitation versus placebo on the primary and key secondary endpoints,” said study investigator George Grossberg, MD, professor and director of the division of geriatric psychiatry, department of psychiatry & behavioral neuroscience, Saint Louis University.

Dr. Grossberg presented the findings as part of the annual meeting of the American Association for Geriatric Psychiatry.

Agitation common, distressing

With two previous studies also showing efficacy of brexpiprazole in AD-related agitation, Dr. Grossberg speculated that brexpiprazole will become the first drug to be approved for agitation in AD.

Agitation is one of the most common AD symptoms and is arguably the most distressing for patients and caregivers alike, Dr. Grossberg noted.

The drug was approved by the Food and Drug Administration in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.

To investigate the drug at effective doses for AD-related agitation, the researchers conducted a phase 3 multicenter trial that included 345 patients with AD who met criteria for agitation and aggression.

Study participants had a mean Mini-Mental State Examination (MMSE) score between 5 and 22 at screening and baseline and a mean Cohen-Mansfield Agitation Inventory (CMAI) total score of about 79. A score above 45 is considered clinically significant agitation. Use of AD medications were permitted.

Patients had a mean age of 74 years and were randomly assigned in a 2:1 ratio to receive treatment with brexpiprazole 2 mg (n = 75) or 3 mg (n = 153) per day, or placebo (n = 117).

The study’s primary endpoint was improvement as assessed by the CMAI. Over 12 weeks, participants in the brexpiprazole group experienced greater improvement in agitation, with a mean change of –22.6 with brexpiprazole vs. –17.3 with placebo (P = .0026).

Brexpiprazole was also associated with significantly greater improvement in the secondary outcome of change from baseline to week 12 in agitation severity, as assessed using the Clinical Global Impression-Severity of Illness (CGI-S) score (mean change, –1.20 with brexpiprazole vs. –0.93 with placebo; P = .0078).

Specifically, treatment with the drug resulted in improvements in three key subscales of agitation, including aggressive behavior, such as physically striking out (P < .01 vs. placebo); physically nonaggressive; and verbally agitated, such as screaming or cursing (both P < .05).

Treatment-emergent adverse events (TEAEs) associated with brexpiprazole vs. placebo included somnolence (3.5% vs. 0.9%), nasopharyngitis (3.1% vs. 1.7%), dizziness (2.7% vs. 1.7%), diarrhea (2.2% vs. 0.9%), urinary tract infection (2.2% vs. 0.9%), and asthenia (2.2% vs. 0.0%).

“Aside from headache, no other TEAEs had an incidence of more than 5% in the brexpiprazole (2 or 3 mg) group, or in either dose group,” Dr. Grossberg said. “Cognition also remained stable,” he added.

Boxed warnings

Adverse events commonly associated with brexpiprazole include weight change, extrapyramidal events, falls, cardiovascular events, and sedation. In the study, all occurred at an incidence of less than 2% in both study groups, he noted.

Compared with the antipsychotic aripiprazole, brexpiprazole is associated with lower weight gain and akathisia, or motor restlessness.

One death occurred in the brexpiprazole 3 mg group in a patient who had heart failure, pneumonia, and cachexia. At autopsy, it was found the patient had cerebral and coronary atherosclerosis. The death was considered to be unrelated to brexpiprazole, said Dr. Grossberg.

This finding is notable because a caveat is that brexpiprazole, like aripiprazole and other typical and atypical antipsychotics, carries an FDA boxed warning related to an increased risk for death in older patients when used for dementia-related psychosis.

Noting that a black box warning about mortality risk is not a minor issue, Dr. Grossberg added that the risks are relatively low, whereas the risks associated with agitation in dementia can be high.

“If it’s an emergency situation, you have to treat the patient because otherwise they may harm someone else, or harm the staff, or harm their loved ones or themselves, and in those cases, we want to treat the patient first, get them under control, and then we worry about the black box,” he said.

In addition, “the No. 1 reason for getting kicked out of a nursing home is agitation or severe behaviors in the context of a dementia or a major neurocognitive disorder that the facility cannot control,” Dr. Grossberg added.

In such cases, patients may wind up in an emergency department and may not be welcome back at the nursing home.

“There’s always a risk/benefit ratio, and I have that discussion with patients and their families, but I can tell you that I’ve never had a family ask me not to use a medication because of the black box warning, because they see how miserable and how out of control their loved one is and they’re miserable because they see the suffering and will ask that we do anything that we can to get this behavior under control,” Dr. Grossberg said.

Caution still warranted

Commenting on the study, Rajesh R. Tampi, MD, professor and chairman of the department of psychiatry and the Bhatia Family Endowed Chair in Psychiatry at Creighton University, Omaha, Neb., underscored that, owing to the concerns behind the FDA warnings, “nonpharmacologic management is the cornerstone of treating agitation in Alzheimer’s dementia.”

He noted that the lack of an FDA-approved drug for agitation with AD is the result of “the overall benefits of any of the drug classes or drugs trialed to treat agitation in Alzheimer’s dementia vs. their adverse effect profile,” he said.

Therefore, he continued, “any medication or medication class should be used with caution among these individuals who often have polymorbidity.”

Dr. Tampi agreed that “the use of each drug for agitation in AD should be on a case-by-case basis with a clear and documented risk/benefit discussion with the patient and their families.”

“These medications should only be used for refractory symptoms or emergency situations where the agitation is not managed adequately with nonpharmacologic techniques and with a clear and documented risk/benefit discussion with patients and their families,” Dr. Tampi said. 

The study was supported by Otsuka Pharmaceutical Development & Commercialization and H. Lundbeck. Dr. Grossberg has received consulting fees from Acadia, Avanir, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda. Dr. Tampi had no disclosures to report.

A version of this article first appeared on Medscape.com.

This article was updated 3/14/23.

NEW ORLEANS - The antipsychotic brexpiprazole effectively improves agitation associated with Alzheimer’s disease (AD) with favorable tolerability, results of a phase 3 study suggest.

“In this phase 3 trial of patients with agitation in Alzheimer’s dementia, treatment with brexpiprazole 2 or 3 mg/day resulted in statistically significantly greater improvements in agitation versus placebo on the primary and key secondary endpoints,” said study investigator George Grossberg, MD, professor and director of the division of geriatric psychiatry, department of psychiatry & behavioral neuroscience, Saint Louis University.

Dr. Grossberg presented the findings as part of the annual meeting of the American Association for Geriatric Psychiatry.

Agitation common, distressing

With two previous studies also showing efficacy of brexpiprazole in AD-related agitation, Dr. Grossberg speculated that brexpiprazole will become the first drug to be approved for agitation in AD.

Agitation is one of the most common AD symptoms and is arguably the most distressing for patients and caregivers alike, Dr. Grossberg noted.

The drug was approved by the Food and Drug Administration in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.

To investigate the drug at effective doses for AD-related agitation, the researchers conducted a phase 3 multicenter trial that included 345 patients with AD who met criteria for agitation and aggression.

Study participants had a mean Mini-Mental State Examination (MMSE) score between 5 and 22 at screening and baseline and a mean Cohen-Mansfield Agitation Inventory (CMAI) total score of about 79. A score above 45 is considered clinically significant agitation. Use of AD medications were permitted.

Patients had a mean age of 74 years and were randomly assigned in a 2:1 ratio to receive treatment with brexpiprazole 2 mg (n = 75) or 3 mg (n = 153) per day, or placebo (n = 117).

The study’s primary endpoint was improvement as assessed by the CMAI. Over 12 weeks, participants in the brexpiprazole group experienced greater improvement in agitation, with a mean change of –22.6 with brexpiprazole vs. –17.3 with placebo (P = .0026).

Brexpiprazole was also associated with significantly greater improvement in the secondary outcome of change from baseline to week 12 in agitation severity, as assessed using the Clinical Global Impression-Severity of Illness (CGI-S) score (mean change, –1.20 with brexpiprazole vs. –0.93 with placebo; P = .0078).

Specifically, treatment with the drug resulted in improvements in three key subscales of agitation, including aggressive behavior, such as physically striking out (P < .01 vs. placebo); physically nonaggressive; and verbally agitated, such as screaming or cursing (both P < .05).

Treatment-emergent adverse events (TEAEs) associated with brexpiprazole vs. placebo included somnolence (3.5% vs. 0.9%), nasopharyngitis (3.1% vs. 1.7%), dizziness (2.7% vs. 1.7%), diarrhea (2.2% vs. 0.9%), urinary tract infection (2.2% vs. 0.9%), and asthenia (2.2% vs. 0.0%).

“Aside from headache, no other TEAEs had an incidence of more than 5% in the brexpiprazole (2 or 3 mg) group, or in either dose group,” Dr. Grossberg said. “Cognition also remained stable,” he added.

Boxed warnings

Adverse events commonly associated with brexpiprazole include weight change, extrapyramidal events, falls, cardiovascular events, and sedation. In the study, all occurred at an incidence of less than 2% in both study groups, he noted.

Compared with the antipsychotic aripiprazole, brexpiprazole is associated with lower weight gain and akathisia, or motor restlessness.

One death occurred in the brexpiprazole 3 mg group in a patient who had heart failure, pneumonia, and cachexia. At autopsy, it was found the patient had cerebral and coronary atherosclerosis. The death was considered to be unrelated to brexpiprazole, said Dr. Grossberg.

This finding is notable because a caveat is that brexpiprazole, like aripiprazole and other typical and atypical antipsychotics, carries an FDA boxed warning related to an increased risk for death in older patients when used for dementia-related psychosis.

Noting that a black box warning about mortality risk is not a minor issue, Dr. Grossberg added that the risks are relatively low, whereas the risks associated with agitation in dementia can be high.

“If it’s an emergency situation, you have to treat the patient because otherwise they may harm someone else, or harm the staff, or harm their loved ones or themselves, and in those cases, we want to treat the patient first, get them under control, and then we worry about the black box,” he said.

In addition, “the No. 1 reason for getting kicked out of a nursing home is agitation or severe behaviors in the context of a dementia or a major neurocognitive disorder that the facility cannot control,” Dr. Grossberg added.

In such cases, patients may wind up in an emergency department and may not be welcome back at the nursing home.

“There’s always a risk/benefit ratio, and I have that discussion with patients and their families, but I can tell you that I’ve never had a family ask me not to use a medication because of the black box warning, because they see how miserable and how out of control their loved one is and they’re miserable because they see the suffering and will ask that we do anything that we can to get this behavior under control,” Dr. Grossberg said.

Caution still warranted

Commenting on the study, Rajesh R. Tampi, MD, professor and chairman of the department of psychiatry and the Bhatia Family Endowed Chair in Psychiatry at Creighton University, Omaha, Neb., underscored that, owing to the concerns behind the FDA warnings, “nonpharmacologic management is the cornerstone of treating agitation in Alzheimer’s dementia.”

He noted that the lack of an FDA-approved drug for agitation with AD is the result of “the overall benefits of any of the drug classes or drugs trialed to treat agitation in Alzheimer’s dementia vs. their adverse effect profile,” he said.

Therefore, he continued, “any medication or medication class should be used with caution among these individuals who often have polymorbidity.”

Dr. Tampi agreed that “the use of each drug for agitation in AD should be on a case-by-case basis with a clear and documented risk/benefit discussion with the patient and their families.”

“These medications should only be used for refractory symptoms or emergency situations where the agitation is not managed adequately with nonpharmacologic techniques and with a clear and documented risk/benefit discussion with patients and their families,” Dr. Tampi said. 

The study was supported by Otsuka Pharmaceutical Development & Commercialization and H. Lundbeck. Dr. Grossberg has received consulting fees from Acadia, Avanir, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda. Dr. Tampi had no disclosures to report.

A version of this article first appeared on Medscape.com.

This article was updated 3/14/23.

Response to buprenorphine among emergency department patients using fentanyl was similar to that in patients using other opioids, based on data from nearly 900 individuals.

California EDs include a facilitation program known as CA Bridge for the treatment of opioid use disorder. Guidelines for CA Bridge call for high-dose buprenorphine to treat patients in drug withdrawal, with doses starting at 8-16 mg, Hannah Snyder, MD, of the University of California, San Francisco, and colleagues wrote.

“Buprenorphine has been repeatedly shown to save lives and prevent overdoses,” Dr. Snyder said in an interview. “We know that emergency department–initiated buprenorphine is an essential tool for increasing access. In the era of fentanyl, both patients and providers have expressed concerns that buprenorphine may not work as well as it did when patients were more likely to be using heroin or opioid pills.

“This retrospective cohort study provides additional information about emergency department buprenorphine as fentanyl becomes increasingly prevalent.” 

In a research letter published in JAMA Network Open, the investigators reviewed data from the electronic health records of 896 patients who presented with opioid use disorder (OUD) at 16 CA Bridge EDs between Jan. 1, 2020, and April 30, 2020. All patients with OUD were included regardless of chief concern, current treatment, treatment desires, or withdrawal. A total of 87 individuals reported fentanyl use; if no fentanyl use was reported, the patient was classified as not using fentanyl. The median age of the patients was 35 years, two thirds were male, approximately 46% were White and non-Hispanic, and 30% had unstable housing.

The primary outcome was follow-up engagement at 7-14 days and 25-37 days.

A total of 492 patients received buprenorphine, including 44 fentanyl users, and 439 initiated high doses of 8-32 mg. At a 30-day follow-up, eight patients had precipitated withdrawal, including two cases in fentanyl users; none of these cases required hospital admission.

The follow-up engagement was similar for both groups, with adjusted odds ratios of 0.60 for administered buprenorphine at the initial ED encounter, 1.09 for 7-day follow-up, and 1.33 for 30-day follow-up.

The findings were limited by the retrospective design and use of clinical documentation, which likely resulted in underreporting of fentanyl use and follow-up, the researchers noted. However, the results supported the effectiveness of buprenorphine for ED patients in withdrawal with a history of fentanyl exposure.

“We were pleased to see that precipitated withdrawal was relatively uncommon in this study, and that patients who did and did not use fentanyl followed up at similar rates,” said Dr. Snyder. “This aligns with our clinical experience and prior research showing that emergency department buprenorphine starts continue to be an essential tool.”

The message for clinicians: “If a patient presents to the emergency department in objective opioid withdrawal and desires buprenorphine, they should be offered treatment in that moment,” Dr. Snyder said. “Treatment protocols used by hospitals in this study are available online. Emergency departments can offer compassionate and evidence-based treatment initiation 24 hours a day, 7 days a week, 365 days a year.”
 

More data needed on dosing strategies

“We need additional research to determine best practices for patients who use fentanyl and want to start buprenorphine, but are not yet in withdrawal,” Dr. Snyder said. “Doses of buprenorphine like those in this study are only appropriate for patients who are in withdrawal with objective signs, so some patients may struggle to wait long enough after their last use to go into sufficient withdrawal.”

Precipitated withdrawal does occur in some cases, said Dr. Snyder. “If it does, the emergency department is a very good place to manage it. We need additional research to determine best practices in management to make patients as comfortable as possible, including additional high-dose buprenorphine as well as additional adjunctive agents.”
 

Findings support buprenorphine

“The classic approach to buprenorphine initiation, which emerged from psychiatry outpatient office visits, is to start with very small doses of buprenorphine [2-4 mg] and titrate up slowly,” Reuben J. Strayer, MD, said in an interview.

“This dose range turns out to be the ‘sour spot’ most likely to cause the most important complication around buprenorphine initiation–precipitated withdrawal,” said Dr. Strayer, the director of addiction medicine in the emergency medicine department at Maimonides Medical Center, New York.

“One of the current focus areas of OUD treatment research is determining how to initiate buprenorphine without entailing a period of spontaneous withdrawal and without causing precipitated withdrawal,” Strayer explained. “The two primary strategies are low-dose buprenorphine initiation [LDBI, less than 2 mg, sometimes called microdosing] and high-dose [HDBI, ≥ 16 mg] buprenorphine initiation. HDBI is attractive because the primary treatment of buprenorphine-precipitated withdrawal is more buprenorphine.

“Additionally, using a high dose up front immediately transitions the patient to therapeutic blood levels, which protects the patient from withdrawal, cravings, and overdose from dangerous opioids (heroin, fentanyl, oxycodone).”

However, “the contamination and now replacement of heroin with fentanyl in the street drug supply has challenged buprenorphine initiation, because fentanyl, when used chronically, accumulates in the body and leaks into the bloodstream slowly over time, preventing the opioid washout that is required to eliminate the risk of precipitated withdrawal when buprenorphine is administered,” said Dr. Strayer.

The current study demonstrates that patients who are initiated with a first dose of 8-16 mg buprenorphine are unlikely to experience precipitated withdrawal and are successfully transitioned to buprenorphine maintenance and clinic follow-up, Dr. Snyder said, but he was surprised by the low rate of precipitated withdrawal in the current study, “which is discordant with what is being anecdotally reported across the country.”

However, the take-home message for clinicians is the support for the initiation of buprenorphine in emergency department settings at a starting dose of 8-16 mg, regardless of reported fentanyl use, he said. “Given the huge impact buprenorphine therapy has on OUD-related mortality, clinicians should make every effort to initiate buprenorphine for OUD patients at every opportunity, and precipitated withdrawal is very unlikely in appropriately selected patients.

“Many clinicians remain reluctant to initiate buprenorphine in ED settings for unfamiliarity with the drug, fear of precipitated withdrawal, or concerns around the certainty of outpatient follow-up,” Dr. Snyder said. “Education, encouragement, systems programming, such as including decision support within the electronic health record, and role-modeling from local champions will promote wider adoption of this lifesaving practice.”

Looking ahead, “more research, including prospective research, is needed to refine best practices around buprenorphine administration,” said Dr. Snyder. Questions to address include which patients are most at risk for precipitated withdrawal and whether there are alternatives to standard initiation dosing that are sufficiently unlikely to cause precipitated withdrawal. “Possibly effective alternatives include buprenorphine initiation by administration of long-acting injectable depot buprenorphine, which accumulates slowly, potentially avoiding precipitated withdrawal, as well as a slow intravenous buprenorphine infusion such as 9 mg given over 12 hours.”

The study received no outside funding. Dr. Snyder disclosed grants from the Substance Abuse and Mental Health Services Administration and the California Department of Health Care Services during the study. Dr. Strayer reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Response to buprenorphine among emergency department patients using fentanyl was similar to that in patients using other opioids, based on data from nearly 900 individuals.

California EDs include a facilitation program known as CA Bridge for the treatment of opioid use disorder. Guidelines for CA Bridge call for high-dose buprenorphine to treat patients in drug withdrawal, with doses starting at 8-16 mg, Hannah Snyder, MD, of the University of California, San Francisco, and colleagues wrote.

“Buprenorphine has been repeatedly shown to save lives and prevent overdoses,” Dr. Snyder said in an interview. “We know that emergency department–initiated buprenorphine is an essential tool for increasing access. In the era of fentanyl, both patients and providers have expressed concerns that buprenorphine may not work as well as it did when patients were more likely to be using heroin or opioid pills.

“This retrospective cohort study provides additional information about emergency department buprenorphine as fentanyl becomes increasingly prevalent.” 

In a research letter published in JAMA Network Open, the investigators reviewed data from the electronic health records of 896 patients who presented with opioid use disorder (OUD) at 16 CA Bridge EDs between Jan. 1, 2020, and April 30, 2020. All patients with OUD were included regardless of chief concern, current treatment, treatment desires, or withdrawal. A total of 87 individuals reported fentanyl use; if no fentanyl use was reported, the patient was classified as not using fentanyl. The median age of the patients was 35 years, two thirds were male, approximately 46% were White and non-Hispanic, and 30% had unstable housing.

The primary outcome was follow-up engagement at 7-14 days and 25-37 days.

A total of 492 patients received buprenorphine, including 44 fentanyl users, and 439 initiated high doses of 8-32 mg. At a 30-day follow-up, eight patients had precipitated withdrawal, including two cases in fentanyl users; none of these cases required hospital admission.

The follow-up engagement was similar for both groups, with adjusted odds ratios of 0.60 for administered buprenorphine at the initial ED encounter, 1.09 for 7-day follow-up, and 1.33 for 30-day follow-up.

The findings were limited by the retrospective design and use of clinical documentation, which likely resulted in underreporting of fentanyl use and follow-up, the researchers noted. However, the results supported the effectiveness of buprenorphine for ED patients in withdrawal with a history of fentanyl exposure.

“We were pleased to see that precipitated withdrawal was relatively uncommon in this study, and that patients who did and did not use fentanyl followed up at similar rates,” said Dr. Snyder. “This aligns with our clinical experience and prior research showing that emergency department buprenorphine starts continue to be an essential tool.”

The message for clinicians: “If a patient presents to the emergency department in objective opioid withdrawal and desires buprenorphine, they should be offered treatment in that moment,” Dr. Snyder said. “Treatment protocols used by hospitals in this study are available online. Emergency departments can offer compassionate and evidence-based treatment initiation 24 hours a day, 7 days a week, 365 days a year.”
 

More data needed on dosing strategies

“We need additional research to determine best practices for patients who use fentanyl and want to start buprenorphine, but are not yet in withdrawal,” Dr. Snyder said. “Doses of buprenorphine like those in this study are only appropriate for patients who are in withdrawal with objective signs, so some patients may struggle to wait long enough after their last use to go into sufficient withdrawal.”

Precipitated withdrawal does occur in some cases, said Dr. Snyder. “If it does, the emergency department is a very good place to manage it. We need additional research to determine best practices in management to make patients as comfortable as possible, including additional high-dose buprenorphine as well as additional adjunctive agents.”
 

Findings support buprenorphine

“The classic approach to buprenorphine initiation, which emerged from psychiatry outpatient office visits, is to start with very small doses of buprenorphine [2-4 mg] and titrate up slowly,” Reuben J. Strayer, MD, said in an interview.

“This dose range turns out to be the ‘sour spot’ most likely to cause the most important complication around buprenorphine initiation–precipitated withdrawal,” said Dr. Strayer, the director of addiction medicine in the emergency medicine department at Maimonides Medical Center, New York.

“One of the current focus areas of OUD treatment research is determining how to initiate buprenorphine without entailing a period of spontaneous withdrawal and without causing precipitated withdrawal,” Strayer explained. “The two primary strategies are low-dose buprenorphine initiation [LDBI, less than 2 mg, sometimes called microdosing] and high-dose [HDBI, ≥ 16 mg] buprenorphine initiation. HDBI is attractive because the primary treatment of buprenorphine-precipitated withdrawal is more buprenorphine.

“Additionally, using a high dose up front immediately transitions the patient to therapeutic blood levels, which protects the patient from withdrawal, cravings, and overdose from dangerous opioids (heroin, fentanyl, oxycodone).”

However, “the contamination and now replacement of heroin with fentanyl in the street drug supply has challenged buprenorphine initiation, because fentanyl, when used chronically, accumulates in the body and leaks into the bloodstream slowly over time, preventing the opioid washout that is required to eliminate the risk of precipitated withdrawal when buprenorphine is administered,” said Dr. Strayer.

The current study demonstrates that patients who are initiated with a first dose of 8-16 mg buprenorphine are unlikely to experience precipitated withdrawal and are successfully transitioned to buprenorphine maintenance and clinic follow-up, Dr. Snyder said, but he was surprised by the low rate of precipitated withdrawal in the current study, “which is discordant with what is being anecdotally reported across the country.”

However, the take-home message for clinicians is the support for the initiation of buprenorphine in emergency department settings at a starting dose of 8-16 mg, regardless of reported fentanyl use, he said. “Given the huge impact buprenorphine therapy has on OUD-related mortality, clinicians should make every effort to initiate buprenorphine for OUD patients at every opportunity, and precipitated withdrawal is very unlikely in appropriately selected patients.

“Many clinicians remain reluctant to initiate buprenorphine in ED settings for unfamiliarity with the drug, fear of precipitated withdrawal, or concerns around the certainty of outpatient follow-up,” Dr. Snyder said. “Education, encouragement, systems programming, such as including decision support within the electronic health record, and role-modeling from local champions will promote wider adoption of this lifesaving practice.”

Looking ahead, “more research, including prospective research, is needed to refine best practices around buprenorphine administration,” said Dr. Snyder. Questions to address include which patients are most at risk for precipitated withdrawal and whether there are alternatives to standard initiation dosing that are sufficiently unlikely to cause precipitated withdrawal. “Possibly effective alternatives include buprenorphine initiation by administration of long-acting injectable depot buprenorphine, which accumulates slowly, potentially avoiding precipitated withdrawal, as well as a slow intravenous buprenorphine infusion such as 9 mg given over 12 hours.”

The study received no outside funding. Dr. Snyder disclosed grants from the Substance Abuse and Mental Health Services Administration and the California Department of Health Care Services during the study. Dr. Strayer reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Response to buprenorphine among emergency department patients using fentanyl was similar to that in patients using other opioids, based on data from nearly 900 individuals.

California EDs include a facilitation program known as CA Bridge for the treatment of opioid use disorder. Guidelines for CA Bridge call for high-dose buprenorphine to treat patients in drug withdrawal, with doses starting at 8-16 mg, Hannah Snyder, MD, of the University of California, San Francisco, and colleagues wrote.

“Buprenorphine has been repeatedly shown to save lives and prevent overdoses,” Dr. Snyder said in an interview. “We know that emergency department–initiated buprenorphine is an essential tool for increasing access. In the era of fentanyl, both patients and providers have expressed concerns that buprenorphine may not work as well as it did when patients were more likely to be using heroin or opioid pills.

“This retrospective cohort study provides additional information about emergency department buprenorphine as fentanyl becomes increasingly prevalent.” 

In a research letter published in JAMA Network Open, the investigators reviewed data from the electronic health records of 896 patients who presented with opioid use disorder (OUD) at 16 CA Bridge EDs between Jan. 1, 2020, and April 30, 2020. All patients with OUD were included regardless of chief concern, current treatment, treatment desires, or withdrawal. A total of 87 individuals reported fentanyl use; if no fentanyl use was reported, the patient was classified as not using fentanyl. The median age of the patients was 35 years, two thirds were male, approximately 46% were White and non-Hispanic, and 30% had unstable housing.

The primary outcome was follow-up engagement at 7-14 days and 25-37 days.

A total of 492 patients received buprenorphine, including 44 fentanyl users, and 439 initiated high doses of 8-32 mg. At a 30-day follow-up, eight patients had precipitated withdrawal, including two cases in fentanyl users; none of these cases required hospital admission.

The follow-up engagement was similar for both groups, with adjusted odds ratios of 0.60 for administered buprenorphine at the initial ED encounter, 1.09 for 7-day follow-up, and 1.33 for 30-day follow-up.

The findings were limited by the retrospective design and use of clinical documentation, which likely resulted in underreporting of fentanyl use and follow-up, the researchers noted. However, the results supported the effectiveness of buprenorphine for ED patients in withdrawal with a history of fentanyl exposure.

“We were pleased to see that precipitated withdrawal was relatively uncommon in this study, and that patients who did and did not use fentanyl followed up at similar rates,” said Dr. Snyder. “This aligns with our clinical experience and prior research showing that emergency department buprenorphine starts continue to be an essential tool.”

The message for clinicians: “If a patient presents to the emergency department in objective opioid withdrawal and desires buprenorphine, they should be offered treatment in that moment,” Dr. Snyder said. “Treatment protocols used by hospitals in this study are available online. Emergency departments can offer compassionate and evidence-based treatment initiation 24 hours a day, 7 days a week, 365 days a year.”
 

More data needed on dosing strategies

“We need additional research to determine best practices for patients who use fentanyl and want to start buprenorphine, but are not yet in withdrawal,” Dr. Snyder said. “Doses of buprenorphine like those in this study are only appropriate for patients who are in withdrawal with objective signs, so some patients may struggle to wait long enough after their last use to go into sufficient withdrawal.”

Precipitated withdrawal does occur in some cases, said Dr. Snyder. “If it does, the emergency department is a very good place to manage it. We need additional research to determine best practices in management to make patients as comfortable as possible, including additional high-dose buprenorphine as well as additional adjunctive agents.”
 

Findings support buprenorphine

“The classic approach to buprenorphine initiation, which emerged from psychiatry outpatient office visits, is to start with very small doses of buprenorphine [2-4 mg] and titrate up slowly,” Reuben J. Strayer, MD, said in an interview.

“This dose range turns out to be the ‘sour spot’ most likely to cause the most important complication around buprenorphine initiation–precipitated withdrawal,” said Dr. Strayer, the director of addiction medicine in the emergency medicine department at Maimonides Medical Center, New York.

“One of the current focus areas of OUD treatment research is determining how to initiate buprenorphine without entailing a period of spontaneous withdrawal and without causing precipitated withdrawal,” Strayer explained. “The two primary strategies are low-dose buprenorphine initiation [LDBI, less than 2 mg, sometimes called microdosing] and high-dose [HDBI, ≥ 16 mg] buprenorphine initiation. HDBI is attractive because the primary treatment of buprenorphine-precipitated withdrawal is more buprenorphine.

“Additionally, using a high dose up front immediately transitions the patient to therapeutic blood levels, which protects the patient from withdrawal, cravings, and overdose from dangerous opioids (heroin, fentanyl, oxycodone).”

However, “the contamination and now replacement of heroin with fentanyl in the street drug supply has challenged buprenorphine initiation, because fentanyl, when used chronically, accumulates in the body and leaks into the bloodstream slowly over time, preventing the opioid washout that is required to eliminate the risk of precipitated withdrawal when buprenorphine is administered,” said Dr. Strayer.

The current study demonstrates that patients who are initiated with a first dose of 8-16 mg buprenorphine are unlikely to experience precipitated withdrawal and are successfully transitioned to buprenorphine maintenance and clinic follow-up, Dr. Snyder said, but he was surprised by the low rate of precipitated withdrawal in the current study, “which is discordant with what is being anecdotally reported across the country.”

However, the take-home message for clinicians is the support for the initiation of buprenorphine in emergency department settings at a starting dose of 8-16 mg, regardless of reported fentanyl use, he said. “Given the huge impact buprenorphine therapy has on OUD-related mortality, clinicians should make every effort to initiate buprenorphine for OUD patients at every opportunity, and precipitated withdrawal is very unlikely in appropriately selected patients.

“Many clinicians remain reluctant to initiate buprenorphine in ED settings for unfamiliarity with the drug, fear of precipitated withdrawal, or concerns around the certainty of outpatient follow-up,” Dr. Snyder said. “Education, encouragement, systems programming, such as including decision support within the electronic health record, and role-modeling from local champions will promote wider adoption of this lifesaving practice.”

Looking ahead, “more research, including prospective research, is needed to refine best practices around buprenorphine administration,” said Dr. Snyder. Questions to address include which patients are most at risk for precipitated withdrawal and whether there are alternatives to standard initiation dosing that are sufficiently unlikely to cause precipitated withdrawal. “Possibly effective alternatives include buprenorphine initiation by administration of long-acting injectable depot buprenorphine, which accumulates slowly, potentially avoiding precipitated withdrawal, as well as a slow intravenous buprenorphine infusion such as 9 mg given over 12 hours.”

The study received no outside funding. Dr. Snyder disclosed grants from the Substance Abuse and Mental Health Services Administration and the California Department of Health Care Services during the study. Dr. Strayer reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

A once-daily oral stimulant medication for treatment of ADHD in individuals aged 6 years or older is safe and effective after 1 year of treatment, new research shows.

Results from a phase 3, multicenter, dose-optimization, open-label safety study of Azstarys (KemPharm) found that most treatment-emergent adverse events (TEAEs) were mild to moderate.

“This data show that Azstarys remains safe and effective for the treatment of ADHD when given for up to a year,” lead investigator Ann Childress, MD, president of the Center for Psychiatry and Behavioral Medicine, Las Vegas, said in an interview.

The study was published online in the Journal of Child and Adolescent Psychopharmacology.
 

Safety at 1 year

The drug is a combination of extended-release serdexmethylphenidate (SDX), KemPharm’s prodrug of dexmethylphenidate, coformulated with immediate-release d-MPH.

SDX is converted to d-MPH after it is absorbed in the gastrointestinal tract. The d-MPH is released gradually throughout the day, providing quick symptom control with the d-MPH and extended control with SDX.

Azstarys was approved by the Food and Drug Administration in 2021 on the basis of results from a laboratory classroom phase 3 trial, which showed significant improvement in ADHD symptoms, compared with placebo.

For this study, the second phase 3 trial of Azstarys, investigators analyzed data from 282 children aged 6-12 years in the United States, including 70 who participated in an earlier 1-month efficacy trial.

After screening and a 3-week dose-optimization phase for new participants, patients received once-daily treatment with doses of 26.1 mg/5.2 mg, 39.2 mg/7.8 mg, or 52.3 mg/10.4 mg of SDX/d-MPH.

After 1 year of treatment, 60.1% of participants reported at least one TEAE, the majority of which were moderate. Twelve patients reported severe TEAEs. Six children (2.5%) discontinued the study because of a TEAE during the treatment phase.

The investigators also measured growth and changes in sleep with the Children’s Sleep Habits Questionnaire during the 12-month study. Sleep improved on most measures and the impact on growth was mild.

There were no life-threatening TEAEs and no deaths reported during the study.

The most common TEAEs during the treatment phase were decreased appetite, upper respiratory tract infection, nasopharyngitis, decreased weight, irritability, and increased weight.
 

Efficacy at 1 year

ADHD symptoms improved considerably after 1 month of treatment, with responses continuing at 1 year.

At baseline, participants’ mean ADHD Rating Scale–5 score was 41.5. After 1 month of treatment, scores averaged 16.1, a decline of –25.3 (P < .001).

The mean score stabilized in the 12-15 range for the remainder of the study. After 1 year of treatment, ADHD symptoms had decreased approximately 70% from baseline.

Investigators found similar results in clinical severity. After 1 month of treatment, the average Clinical Global Impressions–Severity (CGI-S) scale score was 2.5, a decline of –2.2 (P < .0001).

CGI-S scale scores remained in the 2.2-2.4 range for the remainder of the study.

These results, combined with the results of the original classroom trial, suggest Azstarys may offer advantages over other ADHD drugs, Dr. Childress said.

“In the laboratory classroom trial, subjects taking Azstarys completed significantly more math problems than subjects taking placebo beginning at 30 minutes and up to 13 hours after dosing,” Dr. Childress said. “No other methylphenidate extended-release product currently marketed in the United States has a 13-hour duration of effect.”
 

‘Reassuring data’

Commenting on the findings, Aditya Pawar, MD, a child and adolescent psychiatrist with the Kennedy Krieger Institute and an assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said that the study suggests the drug may be a valuable addition to ADHD treatment options for pediatric patients.

“The study provides reassuring data on the safety of stimulants in patients without significant history of cardiac events or blood pressure changes, which are usual concerns among patients and clinicians despite the evidence supporting safety, said Dr. Pawar, who was not part of the study.

“Additionally, the 1-year data on efficacy and safety of a new stimulant medication is valuable for clinicians looking for sustained relief for their patients, despite the limitations of an open-label trial,” she added.

Overall, the safety data reported in the study are fairly consistent with the safety profile of other methylphenidates used for treating ADHD, Dr. Pawar said.

However, she noted, the study does have some limitations, including its open-label design and lack of blinding. The research also excluded children with autism, disruptive mood dysregulation disorders, and other common comorbidities of ADHD, which may limit the generalizability of the results.

“These comorbidities often require stimulants as a part of treatment, and yet have a higher risk of side effects,” Dr. Pawar said. “Future studies with a broader population may be needed to better understand treatment effectiveness and potential risks.”

The study was funded by KemPharm. Dr. Childress serves as consultant for Aardvark, Arbor, Attentive, Cingulate, Ironshore, Neos Therapeutics, Neurocentria, Otsuka, Purdue, Rhodes, Sunovion, Tris Pharma, KemPharm, Supernus, Jazz, Corium, Tulex, and Lumos.

A version of this article first appeared on Medscape.com.

A once-daily oral stimulant medication for treatment of ADHD in individuals aged 6 years or older is safe and effective after 1 year of treatment, new research shows.

Results from a phase 3, multicenter, dose-optimization, open-label safety study of Azstarys (KemPharm) found that most treatment-emergent adverse events (TEAEs) were mild to moderate.

“This data show that Azstarys remains safe and effective for the treatment of ADHD when given for up to a year,” lead investigator Ann Childress, MD, president of the Center for Psychiatry and Behavioral Medicine, Las Vegas, said in an interview.

The study was published online in the Journal of Child and Adolescent Psychopharmacology.
 

Safety at 1 year

The drug is a combination of extended-release serdexmethylphenidate (SDX), KemPharm’s prodrug of dexmethylphenidate, coformulated with immediate-release d-MPH.

SDX is converted to d-MPH after it is absorbed in the gastrointestinal tract. The d-MPH is released gradually throughout the day, providing quick symptom control with the d-MPH and extended control with SDX.

Azstarys was approved by the Food and Drug Administration in 2021 on the basis of results from a laboratory classroom phase 3 trial, which showed significant improvement in ADHD symptoms, compared with placebo.

For this study, the second phase 3 trial of Azstarys, investigators analyzed data from 282 children aged 6-12 years in the United States, including 70 who participated in an earlier 1-month efficacy trial.

After screening and a 3-week dose-optimization phase for new participants, patients received once-daily treatment with doses of 26.1 mg/5.2 mg, 39.2 mg/7.8 mg, or 52.3 mg/10.4 mg of SDX/d-MPH.

After 1 year of treatment, 60.1% of participants reported at least one TEAE, the majority of which were moderate. Twelve patients reported severe TEAEs. Six children (2.5%) discontinued the study because of a TEAE during the treatment phase.

The investigators also measured growth and changes in sleep with the Children’s Sleep Habits Questionnaire during the 12-month study. Sleep improved on most measures and the impact on growth was mild.

There were no life-threatening TEAEs and no deaths reported during the study.

The most common TEAEs during the treatment phase were decreased appetite, upper respiratory tract infection, nasopharyngitis, decreased weight, irritability, and increased weight.
 

Efficacy at 1 year

ADHD symptoms improved considerably after 1 month of treatment, with responses continuing at 1 year.

At baseline, participants’ mean ADHD Rating Scale–5 score was 41.5. After 1 month of treatment, scores averaged 16.1, a decline of –25.3 (P < .001).

The mean score stabilized in the 12-15 range for the remainder of the study. After 1 year of treatment, ADHD symptoms had decreased approximately 70% from baseline.

Investigators found similar results in clinical severity. After 1 month of treatment, the average Clinical Global Impressions–Severity (CGI-S) scale score was 2.5, a decline of –2.2 (P < .0001).

CGI-S scale scores remained in the 2.2-2.4 range for the remainder of the study.

These results, combined with the results of the original classroom trial, suggest Azstarys may offer advantages over other ADHD drugs, Dr. Childress said.

“In the laboratory classroom trial, subjects taking Azstarys completed significantly more math problems than subjects taking placebo beginning at 30 minutes and up to 13 hours after dosing,” Dr. Childress said. “No other methylphenidate extended-release product currently marketed in the United States has a 13-hour duration of effect.”
 

‘Reassuring data’

Commenting on the findings, Aditya Pawar, MD, a child and adolescent psychiatrist with the Kennedy Krieger Institute and an assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said that the study suggests the drug may be a valuable addition to ADHD treatment options for pediatric patients.

“The study provides reassuring data on the safety of stimulants in patients without significant history of cardiac events or blood pressure changes, which are usual concerns among patients and clinicians despite the evidence supporting safety, said Dr. Pawar, who was not part of the study.

“Additionally, the 1-year data on efficacy and safety of a new stimulant medication is valuable for clinicians looking for sustained relief for their patients, despite the limitations of an open-label trial,” she added.

Overall, the safety data reported in the study are fairly consistent with the safety profile of other methylphenidates used for treating ADHD, Dr. Pawar said.

However, she noted, the study does have some limitations, including its open-label design and lack of blinding. The research also excluded children with autism, disruptive mood dysregulation disorders, and other common comorbidities of ADHD, which may limit the generalizability of the results.

“These comorbidities often require stimulants as a part of treatment, and yet have a higher risk of side effects,” Dr. Pawar said. “Future studies with a broader population may be needed to better understand treatment effectiveness and potential risks.”

The study was funded by KemPharm. Dr. Childress serves as consultant for Aardvark, Arbor, Attentive, Cingulate, Ironshore, Neos Therapeutics, Neurocentria, Otsuka, Purdue, Rhodes, Sunovion, Tris Pharma, KemPharm, Supernus, Jazz, Corium, Tulex, and Lumos.

A version of this article first appeared on Medscape.com.

A once-daily oral stimulant medication for treatment of ADHD in individuals aged 6 years or older is safe and effective after 1 year of treatment, new research shows.

Results from a phase 3, multicenter, dose-optimization, open-label safety study of Azstarys (KemPharm) found that most treatment-emergent adverse events (TEAEs) were mild to moderate.

“This data show that Azstarys remains safe and effective for the treatment of ADHD when given for up to a year,” lead investigator Ann Childress, MD, president of the Center for Psychiatry and Behavioral Medicine, Las Vegas, said in an interview.

The study was published online in the Journal of Child and Adolescent Psychopharmacology.
 

Safety at 1 year

The drug is a combination of extended-release serdexmethylphenidate (SDX), KemPharm’s prodrug of dexmethylphenidate, coformulated with immediate-release d-MPH.

SDX is converted to d-MPH after it is absorbed in the gastrointestinal tract. The d-MPH is released gradually throughout the day, providing quick symptom control with the d-MPH and extended control with SDX.

Azstarys was approved by the Food and Drug Administration in 2021 on the basis of results from a laboratory classroom phase 3 trial, which showed significant improvement in ADHD symptoms, compared with placebo.

For this study, the second phase 3 trial of Azstarys, investigators analyzed data from 282 children aged 6-12 years in the United States, including 70 who participated in an earlier 1-month efficacy trial.

After screening and a 3-week dose-optimization phase for new participants, patients received once-daily treatment with doses of 26.1 mg/5.2 mg, 39.2 mg/7.8 mg, or 52.3 mg/10.4 mg of SDX/d-MPH.

After 1 year of treatment, 60.1% of participants reported at least one TEAE, the majority of which were moderate. Twelve patients reported severe TEAEs. Six children (2.5%) discontinued the study because of a TEAE during the treatment phase.

The investigators also measured growth and changes in sleep with the Children’s Sleep Habits Questionnaire during the 12-month study. Sleep improved on most measures and the impact on growth was mild.

There were no life-threatening TEAEs and no deaths reported during the study.

The most common TEAEs during the treatment phase were decreased appetite, upper respiratory tract infection, nasopharyngitis, decreased weight, irritability, and increased weight.
 

Efficacy at 1 year

ADHD symptoms improved considerably after 1 month of treatment, with responses continuing at 1 year.

At baseline, participants’ mean ADHD Rating Scale–5 score was 41.5. After 1 month of treatment, scores averaged 16.1, a decline of –25.3 (P < .001).

The mean score stabilized in the 12-15 range for the remainder of the study. After 1 year of treatment, ADHD symptoms had decreased approximately 70% from baseline.

Investigators found similar results in clinical severity. After 1 month of treatment, the average Clinical Global Impressions–Severity (CGI-S) scale score was 2.5, a decline of –2.2 (P < .0001).

CGI-S scale scores remained in the 2.2-2.4 range for the remainder of the study.

These results, combined with the results of the original classroom trial, suggest Azstarys may offer advantages over other ADHD drugs, Dr. Childress said.

“In the laboratory classroom trial, subjects taking Azstarys completed significantly more math problems than subjects taking placebo beginning at 30 minutes and up to 13 hours after dosing,” Dr. Childress said. “No other methylphenidate extended-release product currently marketed in the United States has a 13-hour duration of effect.”
 

‘Reassuring data’

Commenting on the findings, Aditya Pawar, MD, a child and adolescent psychiatrist with the Kennedy Krieger Institute and an assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said that the study suggests the drug may be a valuable addition to ADHD treatment options for pediatric patients.

“The study provides reassuring data on the safety of stimulants in patients without significant history of cardiac events or blood pressure changes, which are usual concerns among patients and clinicians despite the evidence supporting safety, said Dr. Pawar, who was not part of the study.

“Additionally, the 1-year data on efficacy and safety of a new stimulant medication is valuable for clinicians looking for sustained relief for their patients, despite the limitations of an open-label trial,” she added.

Overall, the safety data reported in the study are fairly consistent with the safety profile of other methylphenidates used for treating ADHD, Dr. Pawar said.

However, she noted, the study does have some limitations, including its open-label design and lack of blinding. The research also excluded children with autism, disruptive mood dysregulation disorders, and other common comorbidities of ADHD, which may limit the generalizability of the results.

“These comorbidities often require stimulants as a part of treatment, and yet have a higher risk of side effects,” Dr. Pawar said. “Future studies with a broader population may be needed to better understand treatment effectiveness and potential risks.”

The study was funded by KemPharm. Dr. Childress serves as consultant for Aardvark, Arbor, Attentive, Cingulate, Ironshore, Neos Therapeutics, Neurocentria, Otsuka, Purdue, Rhodes, Sunovion, Tris Pharma, KemPharm, Supernus, Jazz, Corium, Tulex, and Lumos.

A version of this article first appeared on Medscape.com.

Use of asthma medication by pregnant women was not associated with an increased risk of autism, attention-deficit/hyperactivity disorder, or Tourette syndrome for their children, a new study shows.

The drugs included in the study were leukotriene-receptor antagonists (LTRAs), which are often used to treat allergic airway diseases, including asthma and allergic rhinitis.

“Over the years, the U.S. Food and Drug Administration has monitored post-marketing data about the potential harm of neuropsychiatric events (NEs) associated with montelukast, the first type of LTRAs, and issued boxed warnings about serious mental health side effects for montelukast in 2020,” said corresponding author Tsung-Chieh Yao, MD, of Chang Gung Memorial Hospital, Taiwan, in an interview.

However, evidence of a link between NEs and LTRA use has been inconsistent, according to Dr. Yao and colleagues.

“To date, it remains totally unknown whether the exposure to LTRAs during pregnancy is associated with the risk of neuropsychiatric events in offspring,” said Dr. Yao.

To address this question, the researchers used data from National Health Insurance Research Database in Taiwan to identify pregnant women and their offspring from 2009 to 2019. The initial study population included 576,157 mother-offspring pairs, including 1,995 LTRA-exposed and 574,162 nonexposed children.

The women had a diagnosis of asthma or allergic rhinitis; multiple births and children with congenital malformations were excluded. LTRA exposure was defined as any dispensed prescription for LTRAs during pregnancy. Approximately two-thirds of the mothers were aged 30-40 years at the time of delivery.

The findings were published in a research letter in JAMA Network Open.

In the study population at large, the incidence of the three neurodevelopmental disorders ADHD, autism spectrum disorder (ASD), and Tourette syndrome was not significantly different between those children exposed to LTRAs and those not exposed to LTRAs in utero (1.25% vs. 1.32%; 3.31% vs. 4.36%; and 0.45% vs. 0.83%, respectively).

After propensity score matching, the study population included 1,988 LTRA-exposed children and 19,863 nonexposed children. In this group, no significant associations appeared between prenatal LTRA exposure and the risk of attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.03), autism spectrum disorder (AHR, 1.01), and Tourette syndrome (AHR, 0.63).

Neither duration nor cumulative dose of LTRA use during pregnancy showed an association with ADHD, ASD, or Tourette syndrome in offspring. Duration of LTRA use was categorized as shorter or longer periods of 1-4 weeks vs. more than 4 weeks; cumulative dose was categorized as 1-170 mg vs. 170 mg or higher.

The findings were limited by the lack of randomization, inability to detect long-term risk, and potential lack of generalizability to non-Asian populations, and more research is needed to replicate the results, the researchers noted. However, the current findings were strengthened by the large study population, and suggest that LTRA use in pregnancy does not present a significant risk for NEs in children, which should be reassuring to clinicians and patients, they concluded.

The current study is the first to use the whole of Taiwan population data and extends previous studies by examining the association between LTRA use during pregnancy and risk of neuropsychiatric events in offspring, Dr. Yao said in an interview. “The possibly surprising, but reassuring, finding is that prenatal LTRA exposure did not increase risk of ADHD, ASD, and Tourette syndrome in offspring,” he said.

“Clinicians prescribing LTRAs such as montelukast (Singulair and generics) to pregnant women with asthma or allergic rhinitis may be reassured by our findings,” Dr. Yao added. The results offer real-world evidence to help inform decision-making about the use of LTRAs during pregnancy, although additional research is needed to replicate the study findings in other populations, he said.

The study was supported by the National Health Research Institutes, Taiwan, the Ministry of Science and Technology of Taiwan, the National Science and Technology Council of Taiwan, and the Chang Gung Medical Foundation. The researchers had no financial conflicts to disclose.

Use of asthma medication by pregnant women was not associated with an increased risk of autism, attention-deficit/hyperactivity disorder, or Tourette syndrome for their children, a new study shows.

The drugs included in the study were leukotriene-receptor antagonists (LTRAs), which are often used to treat allergic airway diseases, including asthma and allergic rhinitis.

“Over the years, the U.S. Food and Drug Administration has monitored post-marketing data about the potential harm of neuropsychiatric events (NEs) associated with montelukast, the first type of LTRAs, and issued boxed warnings about serious mental health side effects for montelukast in 2020,” said corresponding author Tsung-Chieh Yao, MD, of Chang Gung Memorial Hospital, Taiwan, in an interview.

However, evidence of a link between NEs and LTRA use has been inconsistent, according to Dr. Yao and colleagues.

“To date, it remains totally unknown whether the exposure to LTRAs during pregnancy is associated with the risk of neuropsychiatric events in offspring,” said Dr. Yao.

To address this question, the researchers used data from National Health Insurance Research Database in Taiwan to identify pregnant women and their offspring from 2009 to 2019. The initial study population included 576,157 mother-offspring pairs, including 1,995 LTRA-exposed and 574,162 nonexposed children.

The women had a diagnosis of asthma or allergic rhinitis; multiple births and children with congenital malformations were excluded. LTRA exposure was defined as any dispensed prescription for LTRAs during pregnancy. Approximately two-thirds of the mothers were aged 30-40 years at the time of delivery.

The findings were published in a research letter in JAMA Network Open.

In the study population at large, the incidence of the three neurodevelopmental disorders ADHD, autism spectrum disorder (ASD), and Tourette syndrome was not significantly different between those children exposed to LTRAs and those not exposed to LTRAs in utero (1.25% vs. 1.32%; 3.31% vs. 4.36%; and 0.45% vs. 0.83%, respectively).

After propensity score matching, the study population included 1,988 LTRA-exposed children and 19,863 nonexposed children. In this group, no significant associations appeared between prenatal LTRA exposure and the risk of attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.03), autism spectrum disorder (AHR, 1.01), and Tourette syndrome (AHR, 0.63).

Neither duration nor cumulative dose of LTRA use during pregnancy showed an association with ADHD, ASD, or Tourette syndrome in offspring. Duration of LTRA use was categorized as shorter or longer periods of 1-4 weeks vs. more than 4 weeks; cumulative dose was categorized as 1-170 mg vs. 170 mg or higher.

The findings were limited by the lack of randomization, inability to detect long-term risk, and potential lack of generalizability to non-Asian populations, and more research is needed to replicate the results, the researchers noted. However, the current findings were strengthened by the large study population, and suggest that LTRA use in pregnancy does not present a significant risk for NEs in children, which should be reassuring to clinicians and patients, they concluded.

The current study is the first to use the whole of Taiwan population data and extends previous studies by examining the association between LTRA use during pregnancy and risk of neuropsychiatric events in offspring, Dr. Yao said in an interview. “The possibly surprising, but reassuring, finding is that prenatal LTRA exposure did not increase risk of ADHD, ASD, and Tourette syndrome in offspring,” he said.

“Clinicians prescribing LTRAs such as montelukast (Singulair and generics) to pregnant women with asthma or allergic rhinitis may be reassured by our findings,” Dr. Yao added. The results offer real-world evidence to help inform decision-making about the use of LTRAs during pregnancy, although additional research is needed to replicate the study findings in other populations, he said.

The study was supported by the National Health Research Institutes, Taiwan, the Ministry of Science and Technology of Taiwan, the National Science and Technology Council of Taiwan, and the Chang Gung Medical Foundation. The researchers had no financial conflicts to disclose.

Use of asthma medication by pregnant women was not associated with an increased risk of autism, attention-deficit/hyperactivity disorder, or Tourette syndrome for their children, a new study shows.

The drugs included in the study were leukotriene-receptor antagonists (LTRAs), which are often used to treat allergic airway diseases, including asthma and allergic rhinitis.

“Over the years, the U.S. Food and Drug Administration has monitored post-marketing data about the potential harm of neuropsychiatric events (NEs) associated with montelukast, the first type of LTRAs, and issued boxed warnings about serious mental health side effects for montelukast in 2020,” said corresponding author Tsung-Chieh Yao, MD, of Chang Gung Memorial Hospital, Taiwan, in an interview.

However, evidence of a link between NEs and LTRA use has been inconsistent, according to Dr. Yao and colleagues.

“To date, it remains totally unknown whether the exposure to LTRAs during pregnancy is associated with the risk of neuropsychiatric events in offspring,” said Dr. Yao.

To address this question, the researchers used data from National Health Insurance Research Database in Taiwan to identify pregnant women and their offspring from 2009 to 2019. The initial study population included 576,157 mother-offspring pairs, including 1,995 LTRA-exposed and 574,162 nonexposed children.

The women had a diagnosis of asthma or allergic rhinitis; multiple births and children with congenital malformations were excluded. LTRA exposure was defined as any dispensed prescription for LTRAs during pregnancy. Approximately two-thirds of the mothers were aged 30-40 years at the time of delivery.

The findings were published in a research letter in JAMA Network Open.

In the study population at large, the incidence of the three neurodevelopmental disorders ADHD, autism spectrum disorder (ASD), and Tourette syndrome was not significantly different between those children exposed to LTRAs and those not exposed to LTRAs in utero (1.25% vs. 1.32%; 3.31% vs. 4.36%; and 0.45% vs. 0.83%, respectively).

After propensity score matching, the study population included 1,988 LTRA-exposed children and 19,863 nonexposed children. In this group, no significant associations appeared between prenatal LTRA exposure and the risk of attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.03), autism spectrum disorder (AHR, 1.01), and Tourette syndrome (AHR, 0.63).

Neither duration nor cumulative dose of LTRA use during pregnancy showed an association with ADHD, ASD, or Tourette syndrome in offspring. Duration of LTRA use was categorized as shorter or longer periods of 1-4 weeks vs. more than 4 weeks; cumulative dose was categorized as 1-170 mg vs. 170 mg or higher.

The findings were limited by the lack of randomization, inability to detect long-term risk, and potential lack of generalizability to non-Asian populations, and more research is needed to replicate the results, the researchers noted. However, the current findings were strengthened by the large study population, and suggest that LTRA use in pregnancy does not present a significant risk for NEs in children, which should be reassuring to clinicians and patients, they concluded.

The current study is the first to use the whole of Taiwan population data and extends previous studies by examining the association between LTRA use during pregnancy and risk of neuropsychiatric events in offspring, Dr. Yao said in an interview. “The possibly surprising, but reassuring, finding is that prenatal LTRA exposure did not increase risk of ADHD, ASD, and Tourette syndrome in offspring,” he said.

“Clinicians prescribing LTRAs such as montelukast (Singulair and generics) to pregnant women with asthma or allergic rhinitis may be reassured by our findings,” Dr. Yao added. The results offer real-world evidence to help inform decision-making about the use of LTRAs during pregnancy, although additional research is needed to replicate the study findings in other populations, he said.

The study was supported by the National Health Research Institutes, Taiwan, the Ministry of Science and Technology of Taiwan, the National Science and Technology Council of Taiwan, and the Chang Gung Medical Foundation. The researchers had no financial conflicts to disclose.

Individuals with a history of depressive symptoms have a 46% higher risk for stroke than those with no depression history, new research suggests.

Data from the international INTERSTROKE study also showed that those with depressive symptoms before a stroke had worse outcomes, including a significantly higher mortality rate in the first month after a stroke.

These findings build on prior research on the link between depression and stroke, including one study that showed an increased risk for incident stroke among those with a high number of depressive symptoms and another that found that worsening depression can precede stroke in older adults.

“Depression is an important risk factor for acute stroke and is potentially a modifiable contributor to the global burden of stroke,” lead investigator Robert Murphy, MB, a consultant in stroke and geriatric medicine and a researcher with the clinical research facility at the University of Galway, Ireland, told this news organization. “Even mild depressive symptoms were found in this study to be associated with increased risk of stroke and this adds to the literature that across the full range of depressive symptoms there is an association with increased risk of stroke.”

The findings were published online March 8 in Neurology.
 

Significant stroke risk

For the analysis, investigators collected data on 26,877 cases and controls across 32 countries who participated in INTERSTROKE, an international case-control study of risk factors for a first acute stroke. Participants were recruited between 2007 and 2015 and completed a series of questionnaires about stroke risk factors, including measures of depressive symptoms experienced in the past 12 months.

After adjustment for occupation, education, wealth index, diet, physical activity, alcohol consumption, and smoking history, having prestroke depressive symptoms was associated with greater odds for acute stroke (adjusted odds ratio [aOR], 1.46; 95% confidence interval [CI], 1.34-1.58), including both intracerebral hemorrhage (aOR, 1.56; 95% CI, 1.28-1.91) and ischemic stroke (aOR, 1.44; 95% CI, 1.31-1.58).

Stroke risk increased with increasing severity of depression, but even those with mild depression had a 35% increased risk (aOR, 1.35; 95% CI, 1.19-1.53).

The increased risk held even after the researchers adjusted further for diabetes, hypertension, atrial fibrillation, and body mass index, and work, home, and financial stress.

The association was consistent across geographical regions and age groups, but was stronger in men and in those without hypertension.

“This study looks at different constructs of depression and identifies that across the spectrum of mild, moderate, and severe depressive symptoms that there is an association present with acute stroke and that a biological gradient emerges with increasing burden of depressive symptoms associated with increasing risk,” Dr. Murphy said.
 

An antidepressant mediating effect?

While prestroke depressive symptoms were not associated with a greater odds of worse stroke severity, they were associated with worse outcomes (P < .001) and higher mortality (10% vs. 8.1%; P = .003) 1 month after a stroke.

In a subgroup analysis, researchers found no association between depressive symptoms and stroke risk in patients who were taking antidepressants.

While no assumptions of causality can be drawn from these findings, “this subgroup analysis does suggest that an increased risk of stroke in those with depression may be attenuated if a patient is on appropriate treatment,” Dr. Murphy said. “This is an area that warrants further exploration.”

The mechanisms that link depression to stroke are unclear, but these findings offer strong evidence that this link exists, Dr. Murphy said.

“We adjusted for potential confounders in sequential models and after adjusting for traditional cardiovascular risk factors there was a consistent association between depressive symptoms and stroke identifying that there is likely an independent association between depression and stroke,” Dr. Murphy said.
 

Questions remain

Commenting on the study, Daniel T. Lackland DrPH, professor, division of translational neurosciences and population studies, department of neurology, Medical University of South Carolina, Charleston, said it adds to a growing body of work on the association of stroke and depression.

“In this case, depression may be a risk factor for having a stroke,” said Dr. Lackland, who was not part of the study. In addition, the study suggests that “treating depression can have additional benefits beyond mental health, in this case, reduced stroke risks.”

However, it’s important, as with any observational study, that there may be confounding factors that may offer an alternative explanation for the findings.

“Further, it is often difficult to accurately assess depression in all individuals, and specifically in individuals who have had a stroke,” Dr. Lackland said. “While this particular study adds depression as a risk factor and suggests treatment of depression in reducing risks, it is important to emphasize that the traditional stroke risk factors including hypertension should [be] continually recognized and treat[ed] with high rigor.”

The INTERSTROKE study was funded by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the Canadian Stroke Network, the Swedish Research Council, the Swedish Heart Lung Foundation, AFA Insurance, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), Merck Sharp & Dohme, the Swedish Heart Lung Foundation, Chest Heart & Stroke Scotland, and the Stroke Association (United Kingdom). Dr. Murphy and Dr. Lackland have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Individuals with a history of depressive symptoms have a 46% higher risk for stroke than those with no depression history, new research suggests.

Data from the international INTERSTROKE study also showed that those with depressive symptoms before a stroke had worse outcomes, including a significantly higher mortality rate in the first month after a stroke.

These findings build on prior research on the link between depression and stroke, including one study that showed an increased risk for incident stroke among those with a high number of depressive symptoms and another that found that worsening depression can precede stroke in older adults.

“Depression is an important risk factor for acute stroke and is potentially a modifiable contributor to the global burden of stroke,” lead investigator Robert Murphy, MB, a consultant in stroke and geriatric medicine and a researcher with the clinical research facility at the University of Galway, Ireland, told this news organization. “Even mild depressive symptoms were found in this study to be associated with increased risk of stroke and this adds to the literature that across the full range of depressive symptoms there is an association with increased risk of stroke.”

The findings were published online March 8 in Neurology.
 

Significant stroke risk

For the analysis, investigators collected data on 26,877 cases and controls across 32 countries who participated in INTERSTROKE, an international case-control study of risk factors for a first acute stroke. Participants were recruited between 2007 and 2015 and completed a series of questionnaires about stroke risk factors, including measures of depressive symptoms experienced in the past 12 months.

After adjustment for occupation, education, wealth index, diet, physical activity, alcohol consumption, and smoking history, having prestroke depressive symptoms was associated with greater odds for acute stroke (adjusted odds ratio [aOR], 1.46; 95% confidence interval [CI], 1.34-1.58), including both intracerebral hemorrhage (aOR, 1.56; 95% CI, 1.28-1.91) and ischemic stroke (aOR, 1.44; 95% CI, 1.31-1.58).

Stroke risk increased with increasing severity of depression, but even those with mild depression had a 35% increased risk (aOR, 1.35; 95% CI, 1.19-1.53).

The increased risk held even after the researchers adjusted further for diabetes, hypertension, atrial fibrillation, and body mass index, and work, home, and financial stress.

The association was consistent across geographical regions and age groups, but was stronger in men and in those without hypertension.

“This study looks at different constructs of depression and identifies that across the spectrum of mild, moderate, and severe depressive symptoms that there is an association present with acute stroke and that a biological gradient emerges with increasing burden of depressive symptoms associated with increasing risk,” Dr. Murphy said.
 

An antidepressant mediating effect?

While prestroke depressive symptoms were not associated with a greater odds of worse stroke severity, they were associated with worse outcomes (P < .001) and higher mortality (10% vs. 8.1%; P = .003) 1 month after a stroke.

In a subgroup analysis, researchers found no association between depressive symptoms and stroke risk in patients who were taking antidepressants.

While no assumptions of causality can be drawn from these findings, “this subgroup analysis does suggest that an increased risk of stroke in those with depression may be attenuated if a patient is on appropriate treatment,” Dr. Murphy said. “This is an area that warrants further exploration.”

The mechanisms that link depression to stroke are unclear, but these findings offer strong evidence that this link exists, Dr. Murphy said.

“We adjusted for potential confounders in sequential models and after adjusting for traditional cardiovascular risk factors there was a consistent association between depressive symptoms and stroke identifying that there is likely an independent association between depression and stroke,” Dr. Murphy said.
 

Questions remain

Commenting on the study, Daniel T. Lackland DrPH, professor, division of translational neurosciences and population studies, department of neurology, Medical University of South Carolina, Charleston, said it adds to a growing body of work on the association of stroke and depression.

“In this case, depression may be a risk factor for having a stroke,” said Dr. Lackland, who was not part of the study. In addition, the study suggests that “treating depression can have additional benefits beyond mental health, in this case, reduced stroke risks.”

However, it’s important, as with any observational study, that there may be confounding factors that may offer an alternative explanation for the findings.

“Further, it is often difficult to accurately assess depression in all individuals, and specifically in individuals who have had a stroke,” Dr. Lackland said. “While this particular study adds depression as a risk factor and suggests treatment of depression in reducing risks, it is important to emphasize that the traditional stroke risk factors including hypertension should [be] continually recognized and treat[ed] with high rigor.”

The INTERSTROKE study was funded by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the Canadian Stroke Network, the Swedish Research Council, the Swedish Heart Lung Foundation, AFA Insurance, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), Merck Sharp & Dohme, the Swedish Heart Lung Foundation, Chest Heart & Stroke Scotland, and the Stroke Association (United Kingdom). Dr. Murphy and Dr. Lackland have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Individuals with a history of depressive symptoms have a 46% higher risk for stroke than those with no depression history, new research suggests.

Data from the international INTERSTROKE study also showed that those with depressive symptoms before a stroke had worse outcomes, including a significantly higher mortality rate in the first month after a stroke.

These findings build on prior research on the link between depression and stroke, including one study that showed an increased risk for incident stroke among those with a high number of depressive symptoms and another that found that worsening depression can precede stroke in older adults.

“Depression is an important risk factor for acute stroke and is potentially a modifiable contributor to the global burden of stroke,” lead investigator Robert Murphy, MB, a consultant in stroke and geriatric medicine and a researcher with the clinical research facility at the University of Galway, Ireland, told this news organization. “Even mild depressive symptoms were found in this study to be associated with increased risk of stroke and this adds to the literature that across the full range of depressive symptoms there is an association with increased risk of stroke.”

The findings were published online March 8 in Neurology.
 

Significant stroke risk

For the analysis, investigators collected data on 26,877 cases and controls across 32 countries who participated in INTERSTROKE, an international case-control study of risk factors for a first acute stroke. Participants were recruited between 2007 and 2015 and completed a series of questionnaires about stroke risk factors, including measures of depressive symptoms experienced in the past 12 months.

After adjustment for occupation, education, wealth index, diet, physical activity, alcohol consumption, and smoking history, having prestroke depressive symptoms was associated with greater odds for acute stroke (adjusted odds ratio [aOR], 1.46; 95% confidence interval [CI], 1.34-1.58), including both intracerebral hemorrhage (aOR, 1.56; 95% CI, 1.28-1.91) and ischemic stroke (aOR, 1.44; 95% CI, 1.31-1.58).

Stroke risk increased with increasing severity of depression, but even those with mild depression had a 35% increased risk (aOR, 1.35; 95% CI, 1.19-1.53).

The increased risk held even after the researchers adjusted further for diabetes, hypertension, atrial fibrillation, and body mass index, and work, home, and financial stress.

The association was consistent across geographical regions and age groups, but was stronger in men and in those without hypertension.

“This study looks at different constructs of depression and identifies that across the spectrum of mild, moderate, and severe depressive symptoms that there is an association present with acute stroke and that a biological gradient emerges with increasing burden of depressive symptoms associated with increasing risk,” Dr. Murphy said.
 

An antidepressant mediating effect?

While prestroke depressive symptoms were not associated with a greater odds of worse stroke severity, they were associated with worse outcomes (P < .001) and higher mortality (10% vs. 8.1%; P = .003) 1 month after a stroke.

In a subgroup analysis, researchers found no association between depressive symptoms and stroke risk in patients who were taking antidepressants.

While no assumptions of causality can be drawn from these findings, “this subgroup analysis does suggest that an increased risk of stroke in those with depression may be attenuated if a patient is on appropriate treatment,” Dr. Murphy said. “This is an area that warrants further exploration.”

The mechanisms that link depression to stroke are unclear, but these findings offer strong evidence that this link exists, Dr. Murphy said.

“We adjusted for potential confounders in sequential models and after adjusting for traditional cardiovascular risk factors there was a consistent association between depressive symptoms and stroke identifying that there is likely an independent association between depression and stroke,” Dr. Murphy said.
 

Questions remain

Commenting on the study, Daniel T. Lackland DrPH, professor, division of translational neurosciences and population studies, department of neurology, Medical University of South Carolina, Charleston, said it adds to a growing body of work on the association of stroke and depression.

“In this case, depression may be a risk factor for having a stroke,” said Dr. Lackland, who was not part of the study. In addition, the study suggests that “treating depression can have additional benefits beyond mental health, in this case, reduced stroke risks.”

However, it’s important, as with any observational study, that there may be confounding factors that may offer an alternative explanation for the findings.

“Further, it is often difficult to accurately assess depression in all individuals, and specifically in individuals who have had a stroke,” Dr. Lackland said. “While this particular study adds depression as a risk factor and suggests treatment of depression in reducing risks, it is important to emphasize that the traditional stroke risk factors including hypertension should [be] continually recognized and treat[ed] with high rigor.”

The INTERSTROKE study was funded by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the Canadian Stroke Network, the Swedish Research Council, the Swedish Heart Lung Foundation, AFA Insurance, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), Merck Sharp & Dohme, the Swedish Heart Lung Foundation, Chest Heart & Stroke Scotland, and the Stroke Association (United Kingdom). Dr. Murphy and Dr. Lackland have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A Michigan physician has been indicted by a federal grand jury on charges of health care fraud and conspiracy to distribute controlled substances.

Sangita Patel, MD, 50, practiced at Advance Medical Home Physicians in Troy.

According to court documents, between July 2020 and June 2022 Patel was responsible for submitting Medicare claims for improper telehealth visits she didn’t conduct herself.

Dr. Patel, who accepted patients who paid in cash as well as those with Medicare and Medicaid coverage, billed approximately $3.4 million to Medicare between 2018 and 2022, according to court documents. An unusual number of these visits were billed using complex codes, an indication of health care fraud. The investigation also found that on many days, Dr. Patel billed for more than 24 hours of services. During this period, according to the document, 76% of Dr. Patel’s Medicare reimbursements were for telehealth.

Prosecutors say that Dr. Patel prescribed Schedule II controlled substances to more than 90% of the patients in these telehealth visits. She delegated her prescription authority to an unlicensed medical assistant. Through undercover visits and cell site search warrant data, the investigation found that Dr. Patel directed patients to contact, via cell phone, this assistant, who then entered electronic prescriptions into the electronic medical records system. Dr. Patel then signed the prescriptions and sent them to the pharmacies without ever interacting with the patients. Prosecutors also used text messages, obtained by search warrant, between Dr. Patel and her assistant and between the assistant and undercover informers to build their case.

Dr. Patel is also accused of referring patients to other providers, who in turn billed Medicare for claims associated with those patients. Advance Medical received $143,000 from these providers, potentially in violation of anti-kickback laws, according to bank records obtained by subpoena.

If convicted, Dr. Patel could be sentenced to up to 10 years in federal prison.

A version of this article first appeared on Medscape.com.

A Michigan physician has been indicted by a federal grand jury on charges of health care fraud and conspiracy to distribute controlled substances.

Sangita Patel, MD, 50, practiced at Advance Medical Home Physicians in Troy.

According to court documents, between July 2020 and June 2022 Patel was responsible for submitting Medicare claims for improper telehealth visits she didn’t conduct herself.

Dr. Patel, who accepted patients who paid in cash as well as those with Medicare and Medicaid coverage, billed approximately $3.4 million to Medicare between 2018 and 2022, according to court documents. An unusual number of these visits were billed using complex codes, an indication of health care fraud. The investigation also found that on many days, Dr. Patel billed for more than 24 hours of services. During this period, according to the document, 76% of Dr. Patel’s Medicare reimbursements were for telehealth.

Prosecutors say that Dr. Patel prescribed Schedule II controlled substances to more than 90% of the patients in these telehealth visits. She delegated her prescription authority to an unlicensed medical assistant. Through undercover visits and cell site search warrant data, the investigation found that Dr. Patel directed patients to contact, via cell phone, this assistant, who then entered electronic prescriptions into the electronic medical records system. Dr. Patel then signed the prescriptions and sent them to the pharmacies without ever interacting with the patients. Prosecutors also used text messages, obtained by search warrant, between Dr. Patel and her assistant and between the assistant and undercover informers to build their case.

Dr. Patel is also accused of referring patients to other providers, who in turn billed Medicare for claims associated with those patients. Advance Medical received $143,000 from these providers, potentially in violation of anti-kickback laws, according to bank records obtained by subpoena.

If convicted, Dr. Patel could be sentenced to up to 10 years in federal prison.

A version of this article first appeared on Medscape.com.

A Michigan physician has been indicted by a federal grand jury on charges of health care fraud and conspiracy to distribute controlled substances.

Sangita Patel, MD, 50, practiced at Advance Medical Home Physicians in Troy.

According to court documents, between July 2020 and June 2022 Patel was responsible for submitting Medicare claims for improper telehealth visits she didn’t conduct herself.

Dr. Patel, who accepted patients who paid in cash as well as those with Medicare and Medicaid coverage, billed approximately $3.4 million to Medicare between 2018 and 2022, according to court documents. An unusual number of these visits were billed using complex codes, an indication of health care fraud. The investigation also found that on many days, Dr. Patel billed for more than 24 hours of services. During this period, according to the document, 76% of Dr. Patel’s Medicare reimbursements were for telehealth.

Prosecutors say that Dr. Patel prescribed Schedule II controlled substances to more than 90% of the patients in these telehealth visits. She delegated her prescription authority to an unlicensed medical assistant. Through undercover visits and cell site search warrant data, the investigation found that Dr. Patel directed patients to contact, via cell phone, this assistant, who then entered electronic prescriptions into the electronic medical records system. Dr. Patel then signed the prescriptions and sent them to the pharmacies without ever interacting with the patients. Prosecutors also used text messages, obtained by search warrant, between Dr. Patel and her assistant and between the assistant and undercover informers to build their case.

Dr. Patel is also accused of referring patients to other providers, who in turn billed Medicare for claims associated with those patients. Advance Medical received $143,000 from these providers, potentially in violation of anti-kickback laws, according to bank records obtained by subpoena.

If convicted, Dr. Patel could be sentenced to up to 10 years in federal prison.

A version of this article first appeared on Medscape.com.